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Leukemia stem cells (LSCs) are widely believed to reside in well-characterized bone marrow (BM) niches; however, the capacity of the BM niches to accommodate LSCs is insufficient, and a significant proportion of LSCs are instead maintained in regions outside the BM. The molecular basis for this niche-independent behavior of LSCs remains elusive. Here, we show that integrin-α9 overexpression (ITGA9 OE) plays a pivotal role in the extramedullary maintenance of LSCs by molecularly mimicking the niche-interacting status, through the binding with its soluble ligand, osteopontin (OPN). Retroviral insertional mutagenesis conducted on leukemia-prone Runx-deficient mice identified Itga9 OE as a novel leukemogenic event. Itga9 OE activates Akt and p38MAPK signaling pathways. The elevated Myc expression subsequently enhances ribosomal biogenesis to overcome the cell integrity defect caused by the preexisting Runx alteration. The Itga9-Myc axis, originally discovered in mice, was further confirmed in multiple human acute myeloid leukemia (AML) subtypes, other than RUNX leukemias. In addition, ITGA9 was shown to be a functional LSC marker of the best prognostic value among 14 known LSC markers tested. Notably, the binding of ITGA9 with soluble OPN, a known negative regulator against HSC activation, induced LSC dormancy, while the disruption of ITGA9-soluble OPN interaction caused rapid cell propagation. These findings suggest that the ITGA9 OE increases both actively proliferating leukemia cells and dormant LSCs in a well-balanced manner, thereby maintaining LSCs. The ITGA9 OE would serve as a novel therapeutic target in AML., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Although it is an effective treatment for acute myeloid leukemia (AML), chemotherapy leads to myelosuppression and poor hematopoietic reconstruction. Hematopoiesis is regulated by bone marrow (BM) endothelial cells (ECs), and BM ECs are dysfunctional in acute leukemia patients with poor hematopoietic reconstitution after allogenic hematopoietic stem cell transplantation. Thus, it is crucial to explore the underlying mechanism of EC impairment and establish strategies for targeted therapy. TGF-β signaling was found to be upregulated in ECs from AML patients in complete remission (CR ECs) and led to CR EC damage. Administration of a TGF-β inhibitor rescued the dysfunction of ECs caused by TGF-β1 expression in vitro, especially their hematopoiesis-supporting ability. Moreover, inhibition of TGF-β expression repaired the BM EC damage triggered by chemotherapy in both AML patients in vitro and in an AML-CR murine model, and restored normal hematopoiesis without promoting AML progression. Mechanistically, our data reveal alterations in the transcriptomic pattern of damaged BM ECs, accompanied by the overexpression of downstream molecules TGF-βR1, pSmad2/3, and functional genes related to adhesion, angiogenesis suppression and pro-apoptosis. Collectively, our findings reveal for the first time that the activation of TGF-β signaling leads to BM EC dysfunction and poor hematopoietic reconstitution. Targeting TGF-β represents a potential therapeutic strategy to promote multilineage hematopoiesis, thereby benefiting more cancer patients who suffer from myelosuppression after chemotherapy., Competing Interests: Declaration of competing interest The authors wish to confirm that there are no known conflicts of interest associated with this publication. All co-authors have seen and approved this version of the manuscript and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Drug resistance is vital for the poor prognosis of acute myeloid leukemia (AML) patients, but the underlying mechanism remains poorly understood. Given the unique microenvironment of bone marrow, we reasoned that drug resistance of AML might rely on distinct metabolic processes. Here, we identify succinate dehydrogenase (SDH) deficiency and over-cumulative succinate as typical features in AML, with a marked function in causing the resistance of AML cells to various anti-cancer therapies. Mechanistically, succinate promotes the accumulation of oncogenic proteins in a manner that precedes transcriptional activation. This function is mediated by succinate-triggered upregulation of ubiquitin-conjugating enzyme E2M (UBC12) phosphorylation, which impairs its E2 function in cullins neddylation. Notably, decreasing succinate by fludarabine can restore the sensitivity of anti-cancer drugs in SDH-deficient AML. Together, we uncover the function of succinate in driving drug resistance by regulating p-UBC12/cullin activity, and indicate reshaping succinate metabolism as a promising treatment for SDH-deficient AML., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Despite significant advances in comprehending its tumorigenic role, the prognostic and therapeutic potential of targeting oxidative phosphorylation (OXPHOS) in acute myeloid leukemia (AML) remain obscure., Methods: The prognostic value of ~ 200 mitochondrial/OXPHOS genes as candidate biomarkers was examined in AML patients over ~ 10 years follow-up using Kaplan-Meier and Cox regression analyses. Furthermore, the transcript levels of the assessed markers were inspected in healthy bone marrow tissues and the dependencies of AML cells on the assessed genes were examined., Results: Elevated levels of NADH:ubiquinone oxidoreductase subunit A6 (NDUFA6), succinate dehydrogenase complex flavoprotein subunit A (SDHA), solute carrier family 25 member 12 (SLC25A12), electron transfer flavoprotein subunit beta (ETFB), carnitine palmitoyltransferase 1A (CPT1A) and glutathione peroxidase 4 (GPX4) were associated with poor overall survival of AML patients. SLC25A12, ETFB and CPT1A were overexpressed in AML compared to healthy tissues. Cytochrome B5 type A (CYB5A) high , SLC25A12 high and GPX4 high AML patients displayed higher levels of circulating and engrafted blasts compared to low-expressing cohorts. NPM1 and SRSF2 mutations were frequent in SDHA low and CPT1A low AML patients respectively. FLT3-ITD, NPM1 and IDH1 mutations were prevalent in CPT1A high AML patients. FLT3-ITD AMLs were more dependent on OXPHOS., Conclusions: This study identifies NDUFA6 and SDHA as novel companion prognostic biomarkers which might present a rational strategy for personalized therapy of AML patients., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Abstract: Menin inhibitors that disrupt the menin-MLL interaction hold promise for treating specific acute myeloid leukemia (AML) subtypes, including those with KMT2A rearrangements (KMT2A-r), yet resistance remains a challenge. Here, through systematic chromatin-focused CRISPR screens, along with genetic, epigenetic, and pharmacologic studies in a variety of human and mouse KMT2A-r AML models, we uncovered a potential resistance mechanism independent of canonical menin-MLL targets. We show that a group of noncanonical menin targets, which are bivalently cooccupied by active menin and repressive H2AK119ub marks, are typically downregulated after menin inhibition. Loss of polycomb repressive complex 1.1 (PRC1.1) subunits, such as polycomb group ring finger 1 (PCGF1) or BCL6 corepressor (BCOR), leads to menin inhibitor resistance by epigenetic reactivation of these noncanonical targets, including MYC. Genetic and pharmacological inhibition of MYC can resensitize PRC1.1-deficient leukemia cells to menin inhibition. Moreover, we demonstrate that leukemia cells with the loss of PRC1.1 subunits exhibit reduced monocytic gene signatures and are susceptible to BCL2 inhibition, and that combinational treatment with venetoclax overcomes the resistance to menin inhibition in PRC1.1-deficient leukemia cells. These findings highlight the important roles of PRC1.1 and its regulated noncanonical menin targets in modulating the menin inhibitor response and provide potential strategies to treat leukemia with compromised PRC1.1 function., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Acute myeloid leukemia (AML) is a rapidly progressing blood cancer. The prognosis of AML can be challenging, emphasizing the need for ongoing research and innovative approaches to improve outcomes in individuals affected by this formidable hematologic malignancy., Methods: In this study, we used single-cell RNA sequencing (scRNA-seq) from AML patients to investigate the impact of L-glutamine metabolism-related genes on disease progression., Results: Our analysis revealed increased glutamine-related activity in CD34 + pre-B cells, suggesting a potential regulatory role in tumorigenesis and AML progression. Furthermore, intercellular communication analysis revealed a significant signaling pathway involving macrophage migration inhibitory factor signaling through CD74 + CD44 within CD34 + pre-B cells, which transmit signals to pre-dendritic cells and monocytes. Ligands for this pathway were predominantly expressed in stromal cells, naïve T cells, and CD34 + pre-B cells. CD74, the pertinent receptor, was predominantly detected in a variety of cellular components, including stromal cells, pre-dendritic cells, plasmacytoid dendritic cells, and hematopoietic progenitors. The study's results provide insights into the possible interplay among these cell types and their collective contribution to the pathogenesis of AML. Moreover, we identified 10 genes associated with AML prognosis, including CCL5, CD52, CFD, FABP5, LGALS1, NUCB2, PSAP, S100A4, SPINK2, and VCAN. Among these, CCL5 and CD52 have been implicated in AML progression and are potential therapeutic targets., Conclusions: This thorough examination of AML biology significantly deepens our grasp of the disease and presents pivotal information that could guide the creation of innovative treatment strategies for AML patients., (© 2024. The Author(s).)

Abstract: B7-H3 (CD276), an immune checkpoint protein of the B7 family, exhibits significant upregulation in solid tumors and hematologic malignancies, exerting a crucial role in their pathophysiology. The distinct differential expression of B7-H3 between tumors and normal tissues and its multifaceted involvement in tumor pathogenesis position it as a promising therapeutic target for tumors. In the context of acute myeloid leukemia (AML), B7-H3 is prominently overexpressed and closely associated with unfavorable prognoses, yet it has remained understudied. Despite various ongoing clinical trials demonstrating the potential efficacy of immunotherapies targeting B7-H3, the precise underlying mechanisms responsible for B7-H3-mediated proliferation and immune evasion in AML remain enigmatic. In view of this, we comprehensively outline the current research progress concerning B7-H3 in AML, encompassing in-depth discussions on its structural attributes, receptor interactions, expression profiles, and biological significance in normal tissues and AML. Moreover, we delve into the protumor effects of B7-H3 in AML, examine the intricate mechanisms that underlie its function, and discuss the emerging application of B7-H3-targeted therapy in AML treatment. By juxtaposing B7-H3 with other molecules within the B7 family, this review emphasizes the distinctive advantages of B7-H3, not only as a valuable prognostic biomarker but also as a highly promising immunotherapeutic target in AML., (Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

BMI1 polycomb ring finger proto-oncogene (BMI1) is involved in the pathogenesis of different cancers, including acute myeloid leukemia (AML). However, the role of the circular RNA of BMI1 (circBMI1) has not been studied. Our study aimed to investigate the role and mechanism of circBMI1 in AML. circBMI1 was significantly decreased in bone marrow mononuclear cells aspirated from patients with AML. Receiver operating characteristic curve analysis showed that circBMI1 could distinguish patients with AML from controls. By overexpressing and knocking down circBMI1 in HL-60 cells, we found that circBMI1 inhibited cell proliferation, promoted apoptosis, and increased chemotherapeutic drug sensitivity in AML. Experiments using severe combined immune-deficient mice and circBMI1 transgenic mice showed that mice with circBMI1 overexpression had lower white blood cell counts, which suggested less severe AML invasion. RNA immunoprecipitation and dual-luciferase reporter assay revealed binding sites among circBMI1, miR-338-5p, and inhibitor of DNA-binding protein 4 (ID4). Rescue experiments proved that circBMI1 inhibited AML progression by binding to miR-338-5p, which affected the expression of ID4. By coculturing exosomes extracted from circBMI1-HL-60 and small interfering circBMI1-HL-60 cells with HL-60 cells, we found that exosomes from circBMI1-HL-60 cells showed tumor-suppressive effects, namely inhibiting HL-60 proliferation, promoting apoptosis, and increasing chemotherapeutic drug sensitivity. Exosomes from small interfering circBMI1-HL-60 cells showed the opposite effects. circBMI1 may act as an exosome-dependent tumor inhibitor. circBMI1, a potential biomarker for clinical diagnosis, acts as a tumor suppressor in AML by regulating miR-338-5p/ID4 and might affect the pathogenesis of AML by exosome secretion., Competing Interests: Conflict of interest statement. The authors declare that they have no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Venetoclax is a BH3 mimetic that was recently approved for the treatment of acute myeloid leukemia (AML) treatment. However, the effect of venetoclax on AML remains limited, and a novel strategy is required. Here, we demonstrate for the first time that the cytotoxic effect of venetoclax drastically increased when by combined with the naturally occurring flavonoid quercetin. Combined treatment with venetoclax and quercetin caused most of AML KG-1 cells to exhibit a condensed morphology. Cell cycle analysis revealed that the combination strongly induced cell death. Caspase inhibitor blocked this cell death, and the combination induced poly (ADP-ribose) polymerase (PARP) cleavage, indicating that apoptosis was the primary mechanism. These effects were also observed in another AML cell line Kasumi-1 but not in chronic myeloid leukemia (CML) K562 cells. Public data analysis demonstrated that B-cell/CLL lymphoma 2 (Bcl-2) expression is increased in AML cells compared to other malignant tumors, and the survival and the growth of AML cell line depends on Bcl-2. We found that quercetin increased Bcl-2-associated X protein (Bax) expression in KG-1. Our study provides a novel function for quercetin and presents a promising strategy for AML treatment using venetoclax., (© 2024. The Author(s).)

Mutation of isocitrate dehydrogenase 2 (IDH2) is a key factor in promoting cytarabine (Ara-C) resistance in acute myeloid leukemia (AML), however the underly mechanism remains unclear. Acute myeloid leukemia cells, were cultured with either IDH2 knockdown (KD-IDH2) or overexpression (OE-IDH2) to elucidate the role of IDH2 in these leukemic cell lines. Additionally, mutant cell lines were engineered to replicate clinically relevant IDH2 mutations. To investigate cellular responses, the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) was administered to the cells. Cell proliferation was quantified using a Cell Counting Kit-8 (CCK-8), while apoptosis was evaluated through propidium iodide staining followed by flow cytometry. Glycolytic metabolism levels were measured using a specific reagent kit, and Western blotting was employed to determine the expression levels of glycolysis-related proteins. Transcriptome sequencing was conducted to elucidate the mechanisms by which IDH2 mutations influence glycolysis. Furthermore, both in vitro cell experiments and in vivo subcutaneous transplantation tumor models in nude mice were utilized to validate these mechanisms. OE-IDH2 in AML cells, enhances resistance to the Ara-C, promotes cell proliferation and glycolysis, and inhibits apoptosis. KD-IDH2 exhibits opposite effects. Both IDH2 mutations and OE-IDH2 produce similar effects on these cellular processes. The increase in glycolysis levels following IDH2 mutation may contribute to the reduced efficacy of Enasidenib in inhibiting the proliferation of IDH-mutant AML cells. Transcriptome sequencing results indicate an enrichment of the PI3K/Akt signaling pathway in IDH2-mutant AML cells. BEZ235 significantly inhibits the expression of phosphorylated PI3K (p-PI3K), phosphorylated Akt (p-Akt), mTOR, glycolytic metabolism, and Ara-C resistance both in vitro and in vivo. Overexpression and mutation of IDH2 coordinate with the Warburg effect through the PI3K/Akt/mTOR pathway to promote Ara-C resistance in AML., (© 2024 The Author(s). Hematological Oncology published by John Wiley & Sons Ltd.)

Background/aim: Aberrant activation of the Wnt/β-catenin signaling pathway contributes to the pathogenesis of acute myelogenous leukemia (AML). Thus, targeting this pathway offers a promising therapeutic strategy against AML. Here, we synthesized a novel dipeptide-type inhibitor of the Wnt/β-catenin signaling pathway, compound #41, and explored its anti-tumor effects on AML cells., Materials and Methods: We evaluated the inhibitory effect of compound #41 on T cell factor (TCF)/β-catenin transcriptional activity using a luciferase (Luc) reporter assay. The anti-tumor effects were assessed on KG1a and MV4;11 human AML cells using RT-qPCR, western blotting, and WST-8, cell cycle, and apoptosis assays. Differentially expressed genes were analyzed by RNA-sequencing (RNA-seq). Additionally, we investigated the in vivo effects of compound #41 using KG1a-Luc/GFP cells in an orthotopic mouse model., Results: The Luc reporter assay showed that compound #41 decreased the TCF/β-catenin transcriptional activity. Compound #41 blocked the cell cycle progression, inhibited cell proliferation, and induced apoptosis in AML cells. Treatment with compound #41 down-regulated the expression of β-catenin, Survivin, and β-catenin-specific target genes, as demonstrated by RNA-seq. In vivo analysis showed that compound #41 blocked the expansion of KG1a-Luc/GFP cells in the bone marrow and prolonged the overall survival of KG1a-Luc/GFP-transplanted mice., Conclusion: Compound #41 suppressed the Wnt/β-catenin signaling pathway by reducing CTNNB1 levels and induced apoptosis in AML cells. Furthermore, compound #41 inhibited the proliferation of KG1a-Luc/GFP cells in the bone marrow and extended the overall survival of mice. Thus, compound #41 is an attractive Wnt/β-catenin signaling pathway inhibitor of AML., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Acute myeloid leukemia (AML) is a hematological malignancy with a high relapse rate and a poor survival rate. The circular RNA circPVT1 and myocyte enhancer factor 2A (MEF2A) have unique functions in the progression of AML; however, the underlying mechanisms and clinical significance remain to be clarified. Bioinformatics and database analyses were used to assess the transcription factors and target genes of circPVT1. Dual‑luciferase reporter gene and argonaute 2‑RNA immunoprecipitation assays were used to verify the targeted relationships. The expression levels of related genes and proteins were detected by reverse transcription‑quantitative PCR and western blotting. Cell viability and apoptosis were detected by Cell Counting Kit‑8 assay and flow cytometry, respectively. The results revealed that circPVT1 was highly expressed in AML samples and cell lines, and that MEF2A regulated the expression of circPVT1. MEF2A overexpression promoted cell viability and epithelial‑mesenchymal transition (EMT), and inhibited cell apoptosis. In addition, circPVT1 was revealed to target the regulation of microRNA (miR)‑455‑3p, and miR‑455‑3p targeted the regulation of MCL1 expression, thus indicating that circPVT1 promoted MCL1 expression through its interaction with miR‑455‑3p. Furthermore, cells were transfected with the small interfering RNA‑(si)‑circPVT1, miR‑455‑3p inhibitor or si‑MCL1, and si‑circPVT1 and si‑MCL1 inhibited the viability and EMT of NB4 and HL‑60 cells. However, the miR‑455‑3p inhibitor had the opposite effect on cells. In conclusion, MEF2A may act as a transcription factor of circPVT1 to promote the malignant process of AML, and knockdown of circPVT1 could inhibit the viability and EMT of AML cells through the miR‑455‑3p/MCL1 axis.

Acute myeloid leukemia (AML) cells are highly dependent on oxidative phosphorylation and the mitochondrial dynamics regulated by fusion-related genes MFN1, MFN2, and OPA1 and fission-related genes DNM1L and MFF. An analysis of previously published gene expression datasets showed that high expression of MFF was significantly associated with poor prognosis in patients with AML. Based on this finding, we investigated the impact of mitochondrial dynamics in AML. Transduction of shRNA against fission-related genes, DNM1L and MFF, inhibited growth and increased the mitochondrial area in AML cell lines. Extracellular flux analysis showed that deletion of mitochondrial dynamic regulators reduced mitochondrial respiration without significantly affecting glycolysis, except in shDNM1L-transfected cells. Immunodeficient NOG mice transplanted with DNM1L- or MFF-knockdown AML cells survived significantly longer than controls. Treatment of AML cell lines with Mdivi-1, which inhibits the DRP1 encoded by DNM1L, inhibited cell proliferation and oxidative phosphorylation. Our results show that mitochondrial dynamics play an important role in AML, and provide novel biological insights. The inhibition of mitochondrial dynamics induces unique mitochondrial alterations, which may be explored as a potential therapeutic target in AML., (© 2024. Japanese Society of Hematology.)

Acute myeloid leukemia (AML) is a heterogeneous group of hematological malignancies characterized by differentiation arrest, high relapse rates, and poor survival. The bone marrow (BM) microenvironment is recognized as a critical mediator of drug resistance and a primary site responsible for AML relapse. Our previous study reported that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr) induces AML cell differentiation by inhibiting pyrimidine synthesis and activating Checkpoint kinase 1. Although the protective effect of BM stroma on leukemia cells in response to cytotoxic drugs is well-documented, its effect on AML differentiation remains less explored. In this study, we investigated the impact of stromal cell lines and primary mesenchymal stromal cells (MSCs) on AML cell line differentiation triggered by AICAr and brequinar, a known dihydroorotate dehydrogenase (DHODH) inhibitor. Our findings indicate that the mouse MS-5 stromal cell line, known for its cytoprotective effects, does not inhibit AML cell differentiation induced by pyrimidine synthesis inhibitors. Interestingly, AICAr caused morphological changes and growth arrest in MS-5 stromal cells via an AMP-activated protein kinase (AMPK)-dependent pathway. Human stromal cell lines HS-5 and HS-27, as well as primary MSCs isolated from patient bone marrow, were superior in promoting AML differentiation compared with mouse cells in response to AICAr and brequinar, with the inhibitors not significantly affecting the stromal cells themselves. In conclusion, our study highlights the supportive role of human BM MSCs in enhancing the differentiation effects of pyrimidine synthesis inhibitors on AML cells, suggesting that AML treatment strategies focusing on differentiation rather than cell killing may be successful in clinical settings. NEW & NOTEWORTHY This study is the first to demonstrate that human stromal cell lines and primary mesenchymal stromal cells from patients enhance the in vitro differentiation of acute myeloid leukemia (AML) cells induced by pyrimidine synthesis inhibitors, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr), and brequinar. Furthermore, this is the first report to show that AICAr affects mouse bone marrow stromal cells by activating AMP-activated protein kinase (AMPK) and that human stromal cells are superior to mouse cells for testing the effects of drugs on AML differentiation.

Enhanced ribosome biogenesis and protein synthesis are required for cell proliferation. During hematopoietic regeneration, hematopoietic stem cells (HSCs) proliferate rapidly to replenish the hematopoietic system. How HSCs respond and regulate ribosome biogenesis and protein synthesis during regeneration remains unclear. Here, we analyzed the expression of a series of ubiquitin-specific-proteases (USPs) during HSC regeneration. We found USP4 expression is significantly increased in proliferating HSCs. Further functional and mechanistic investigations revealed a crucial regulatory function of USP4 in HSC regeneration and leukemia progression by modulating ribosome biogenesis and protein synthesis. USP4 deubiquitinates and stabilizes PES1 to facilitate ribosome biogenesis and protein synthesis in proliferative HSCs and leukemic cells. Usp4 deletion significantly decreases protein synthesis, proliferation and reconstitution capacity of HSCs. Usp4 inhibition suppresses ribosome biogenesis and proliferation of leukemic cells, and prolongs the survival of AML (Acute myeloid leukemia) mice. These findings provide a new insight into the response mechanism of ribosome biogenesis and protein synthesis in HSCs, and their contribution to leukemia progression., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Licochalcone A (Lico A), a naturally bioactive flavonoid, has shown antitumor activity in several types of cancers. However, few studies have focused on its effect on acute myeloid leukemia (AML). Cell viability and colony formation potential were detected by CCK-8 assay and colony formation assay, respectively. Cell cycle distribution and apoptosis were assessed by flow cytometry. Ferroptosis was assessed by measuring reactive oxygen species (ROS), lipid ROS, malondialdehyde (MDA), and glutathione (GSH). Protein expression levels were determined by immunoblotting and immunohistochemistry (IHC), and mRNA expression was detected by real-time qPCR. The m 6 A modification of MDM2 mRNA was verified by methylated RNA immunoprecipitation (MeRIP) assay, and the interaction of IGF2BP3 and MDM2 mRNA was analyzed by RIP assay. Actinomycin D was used to evaluate mRNA stability. The efficacy of Lico A in vivo was examined by a murine xenograft model. Lico A suppressed cell proliferation and induced ferroptosis in MOLM-13 and U-937 in vitro, and slowed the growth of xenograft tumors in vivo. IGF2BP3 was highly expressed in human AML specimens and cells, and Lico A suppressed IGF2BP3 expression in AML cells. Lico A exerted the anti-proliferative and pro-ferroptosis effects by downregulating IGF2BP3. Moreover, IGF2BP3 enhanced the stability and expression of MDM2 mRNA through an m6A-dependent manner. Downregulation of IGF2BP3 impeded AML cell proliferation and enhanced ferroptosis via repressing MDM2. Furthermore, Lico A could affect the MDM2/p53 pathway by downregulating IGF2BP3 expression. Lico A exerts the anti-proliferative and pro-ferroptosis activity in AML cells by affecting the IGF2BP3/MDM2/p53 pathway, providing new evidence for Lico A as a promising agent for the treatment of AML., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Extensive research on the CXCL12-CXCR4 axis in acute myeloid leukemia (AML) has resulted in the incorporation of novel anti-leukemia drugs targeting this axis into therapeutic strategies. However, despite this progress, a comprehensive and up-to-date review addressing the role of the CXCL12-CXCR4 axis in AML's oncogenic processes is lacking. In this review, we examine its molecular aspects influencing cancer progression, such as its impact on autonomous proliferation, apoptotic regulation, chemoresistance mechanisms, and interactions with non-leukemic cells such as MSCs and T reg cells. Additionally, we explore clinical implications, including prognosis, correlation with WBC count, blast count in the bone marrow and peripheral blood, as well as its association with FLT3-ITD, NPM1 mutations, and FAB classification. Finally, this paper extensively discusses drugs that specifically target the CXCL12-CXCR4 axis, including plerixafor/AMD3100, ulocuplumab, peptide E5, and motixafortide, shedding light on their potential therapeutic value in the treatment of AML., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Acute myeloid leukemia (AML) is a predominant form of leukemia. Central nervous system (CNS) involvement complicates its diagnosis due to limited diagnostic tools, as well as its treatment due to inadequate therapeutic methodologies and poor prognosis. Furthermore, its incidence rate is unclear. The mechanisms of AML cell mobilization from the bone marrow (BM) to the CNS are not fully elucidated, and the molecular factors contributing to CNS infiltration are insufficiently recognized. The present review aimed to enhance the understanding of CNS involvement of AML and its impact on CNS. The latest research on the pathways and mechanisms facilitating AML cells to escape the BM and infiltrate the CNS was reviewed. Additionally, novel therapeutic strategies targeting specific molecules and genes for treating CNS involvement in AML were examined.

Identification of specific and therapeutically actionable vulnerabilities, ideally present across multiple mutational backgrounds, is needed to improve acute myeloid leukemia (AML) patients' outcomes. We identify stearoyl-CoA desaturase (SCD), the key enzyme in fatty acid (FA) desaturation, as prognostic of patients' outcomes and, using the clinical-grade inhibitor SSI-4, show that SCD inhibition (SCDi) is a therapeutic vulnerability across multiple AML models in vitro and in vivo. Multiomic analysis demonstrates that SCDi causes lipotoxicity, which induces AML cell death via pleiotropic effects. Sensitivity to SCDi correlates with AML dependency on FA desaturation regardless of mutational profile and is modulated by FA biosynthesis activity. Finally, we show that lipotoxicity increases chemotherapy-induced DNA damage and standard chemotherapy further sensitizes AML cells to SCDi. Our work supports developing FA desaturase inhibitors in AML while stressing the importance of identifying predictive biomarkers of response and biologically validated combination therapies to realize their full therapeutic potential., (© 2024. The Author(s).)

Wilms' tumour 1 (WT1) can function as an oncogene or a tumour suppressor. Our previous clinical cohort studies showed that low WT1 expression at diagnosis independently predicted poor outcomes in acute myeloid leukaemia (AML) with RUNX1::RUNX1T1, whereas it had an opposite role in AML with non-favourable cytogenetic risk (RUNX1::RUNX1T1-deficient). The molecular mechanism by which RUNX1::RUNX1T1 affects the prognostic significance of WT1 in AML remains unknown. In the present study, first we validated the prognostic significance of WT1 expression in AML. Then by using the established transfected cell lines and xenograft tumour model, we found that WT1 suppresses proliferation and enhances effect of cytarabine in RUNX1::RUNX1T1(+) AML but has opposite functions in AML cells without RUNX1::RUNX1T1. Furthermore, as a transcription factor, WT1 physically interacts with RUNX1::RUNX1T1 and acts as a co-factor together with RUNX1::RUNX1T1 to activate the expression of its target gene DUSP6 to dampen extracellular signal-regulated kinase (ERK) activity. When RUNX1::RUNX1T1-deficient, WT1 can activate the mitogen-activated extracellular signal-regulated kinase/ERK axis but not through targeting DUSP6. These results provide a mechanism by which WT1 together with RUNX1::RUNX1T1 suppresses cell proliferation through WT1/DUSP6/ERK axis in AML. The current study provides an explanation for the controversial prognostic significance of WT1 expression in AML patients., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Treatment of acute leukemia is gradually moving away from a "one-size-fits-all" approach, as scientific and clinical advances expand the arsenal of available targeted therapies. One of the recent additions is the group of menin inhibitors; oral, selective, small molecules that disrupt the interaction between the chromatin adapter menin, and an epigenetic regulator, the lysine methyltransferase 2A (KMT2A) complex. Two susceptible leukemia subtypes have been identified: (i) acute myeloid leukemia with a mutation in nucleophosmin 1 (NPM1), and (ii) any acute leukemia, myeloid or lymphoid, with a translocation resulting in the rearrangement of KMT2A. These leukemias share a distinct genetic expression, maintained by the KMT2A-menin interaction. Together they account for approximately 40% of patients with acute myeloid leukemia and 10% of patients with acute lymphoblastic leukemia. This spotlight review follows the journey of revumenib, as a representative of menin inhibitors, from bench to bedside. It focuses on the pathophysiology of leukemias sensitive to menin inhibition, delineation of how this understanding led to targeted drug development, and data from clinical trials. The important discovery of resistance mechanisms is also explored, as well as future directions in the use of menin inhibitors for treating leukemia.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While induction chemotherapy leads to remission in most patients, a significant number will experience relapse. Therefore, there is a need for novel therapies that can improve remission rates in patients with relapsed and refractory AML. CD70 is the natural ligand for CD27 (a member of the TNF superfamily) and appears to be a promising therapeutic target. Consequently, there is considerable interest in developing chimeric antigen receptor (CAR) T-cell therapy products that can specifically target CD70 in various neoplasms, including AML. In this study, we employed routine diagnostic techniques, such as immunohistochemistry and flow cytometry, to investigate the expression of CD70 in bone marrow samples from treatment-naïve and relapsed AML patients after hypomethylating agents (HMA). Also, we evaluated the impact of HMA on CD70 expression and examined CD70 expression in various leukemic cell subsets and normal hematopoietic progenitors., (© 2024. The Author(s).)

As an evolutionarily conserved transcription factor, Cut-like homeobox 1 (CUX1) plays crucial roles in embryonic and nervous system development, cell differentiation, and DNA damage repair. One of its major isoforms, p110CUX1, exhibits stable DNA binding capabilities and contributes to the regulation of cell cycle progression, proliferation, migration, and invasion. While p110CUX1 has been implicated in the progression of various malignant tumors, its involvement in acute myeloid leukemia (AML) remains uncertain. This study aims to elucidate the role of p110CUX1 in AML. Our findings reveal heightened expression levels of both p110CUX1 and pyridoxal phosphatase (PDXP) in AML cell lines. Overexpression of p110CUX1 promotes AML cell proliferation while inhibiting apoptosis and differentiation, whereas knockdown of PDXP yields contrasting effects. Mechanistically, p110CUX1 appears to facilitate AML development by upregulating PDXP expression and activating the PI3K/AKT/mTOR signaling pathway. Animal experimental corroborate the pro-AML effect of p110CUX1. These results provide experimental evidence supporting the involvement of the p110CUX1-PDXP-PI3K/AKT/mTOR axis in AML progression. Hence, targeting p110CUX1 may hold promise as a therapeutic strategy for AML., (© 2024 Wiley Periodicals LLC.)

Deep single-cell multi-omic profiling offers a promising approach to understand and overcome drug resistance in relapsed or refractory (rr) acute myeloid leukemia (AML). Here, we combine single-cell ex vivo drug profiling (pharmacoscopy) with single-cell and bulk DNA, RNA, and protein analyses, alongside clinical data from 21 rrAML patients. Unsupervised data integration reveals reduced ex vivo response to the Bcl-2 inhibitor venetoclax (VEN) in patients treated with both a hypomethylating agent (HMA) and VEN, compared to those pre-exposed to chemotherapy or HMA alone. Integrative analysis identifies both known and unreported mechanisms of innate and treatment-related VEN resistance and suggests alternative treatments, like targeting increased proliferation with the PLK inhibitor volasertib. Additionally, high CD36 expression in VEN-resistant blasts associates with sensitivity to CD36-targeted antibody treatment ex vivo. This study demonstrates how single-cell multi-omic profiling can uncover drug resistance mechanisms and treatment vulnerabilities, providing a valuable resource for future AML research., (© 2024. The Author(s).)

Chromosomal translocations involving the mixed-lineage leukemia (MLL) locus generate potent oncogenic fusion proteins (oncoproteins) that disrupt regulation of developmental gene expression. By profiling the oncoprotein-target sites of 36 broadly representative MLL-rearranged leukemia samples, including three samples that underwent a lymphoid-to-myeloid lineage-switching event in response to therapy, we find the genomic enrichment of the oncoprotein is highly variable between samples and subject to dynamic regulation. At high levels of expression, the oncoproteins preferentially activate either an acute lymphoblastic leukemia (ALL) program, enriched for pro-B-cell genes, or an acute myeloid leukemia (AML) program, enriched for hematopoietic-stem-cell genes. The fusion-partner-specific-binding patterns over these gene sets are highly correlated with the prevalence of each mutation in ALL versus AML. In lineage-switching samples the oncoprotein levels are reduced and the oncoproteins preferentially activate granulocyte-monocyte progenitor (GMP) genes. In a sample that lineage switched during treatment with the menin inhibitor revumenib, the oncoprotein and menin are reduced to undetectable levels, but ENL, a transcriptional cofactor of the oncoprotein, persists on numerous oncoprotein-target loci, including genes in the GMP-like lineage-switching program. We propose MLL oncoproteins promote lineage-switching events through dynamic chromatin binding at lineage-specific target genes, and may support resistance to menin inhibitors through similar changes in chromatin occupancy., (© 2024. The Author(s).)

Acute myeloid leukemia (AML) is a malignant tumor with high recurrence and refractory rates and low survival rates. Increased glycolysis is characteristic of metabolism in AML blast cells and is also associated with chemotherapy resistance. The purpose of this study was to use gene expression and clinical information from The Cancer Genome Atlas (TCGA) database to identify subtypes of AML associated with lactate metabolism. Two different subtypes linked to lactate metabolism, each with specific immunological features and consequences for prognosis, were identified in this study. Using the TCGA and International Cancer Genome Consortium (GEO) cohorts, a prognostic model composed of genes (LMNA, RETN and HK1) for the prognostic value of the lactate metabolism-related risk score prognostic model was created and validated, suggesting possible therapeutic uses. Additionally, the diagnostic value of the prognostic model genes was explored. LMNA and HK1 were ultimately identified as hub genes, and their roles in AML were determined through immune infiltration, GeneMANIA, GSEA, methylation analysis and single-cell analysis. LMNA was upregulated in AML associating with a poor prognosis while HK1 was downregulated in AML associating with a favorable prognosis. The findings underscore the noteworthy impact of genes linked to lactate metabolism in AML and illustrate the possible therapeutic usefulness of the lactate metabolism-related risk score and the hub lactate metabolism-related genes in guiding AML patients' treatment choices., (© 2024. The Author(s).)

Acute myeloid leukemia (AML) emerges as one of the most common and fatal leukemias. Treatment of the disease remains highly challenging owing to profound metabolic rewiring mechanisms that confer plasticity to AML cells, ultimately resulting in therapy resistance. Autophagy, a highly conserved lysosomal-driven catabolic process devoted to macromolecular turnover, displays a dichotomous role in AML by suppressing or promoting disease development and progression. Glycolytic metabolism represents a pivotal strategy for AML cells to sustain increasing energy needs related to uncontrolled growth during disease progression. In this study, we tested the hypothesis that a high glycolytic rate and low autophagy flux could represent an advantage for AML cell proliferation and thus be detrimental for patient's prognosis, and vice versa. TCGA in silico analysis of the AML cohort shows that the high expression of MAP1LC3B (along with that of BECN1 and with low expression of p62 / SQSTM1 ) and the high expression of BNIP3 (along with that of PRKN and of MAP1LC3B ), which together are indicative of increased autophagy and mitophagy, correlate with better prognosis. On the other hand, the high expression of glycolytic markers HK2 , PFKM , and PKM correlates with poor prognosis. Most importantly, the association of a low expression of glycolytic markers with a high expression of autophagy-mitophagy markers conferred the longest overall survival for AML patients. Transcriptomic analysis showed that this combined signature correlates with the downregulation of a subset of genes required for the differentiation of myeloid cells, lactate/pyruvate transporters, and cell cycle progression, in parallel with the upregulation of genes involved in autophagy/lysosomal trafficking and proteolysis, anti-tumor responses like beta-interferon production, and positive regulation of programmed cell death. Taken together, our data support the view that enhanced autophagy-mitophagy flux together with low glycolytic rate predisposes AML patients to a better clinical outcome, suggesting that autophagy inducers and glucose restrictors may hold potential as adjuvant therapeutics for improving AML management.

Rho-associated coiled-coil kinase 2 (ROCK2) is classified as a member of the serine/threonine protein kinase family and has been identified as a key driver of the development of various forms of cancer. The cause of ROCK2's impact on acute myeloid leukemia (AML) is still unknown. We found that ROCK2 expression was higher in AML patients, leading to lower complete response rates and worse overall survival. Additionally, ROCK2 expression was elevated in the doxorubicin-resistant leukemia cell line HL-60/ADM when compared to their individual parent cells. Moreover, the suppression or inhibition of ROCK2 leads to enhanced drug sensitivity in both AML cell lines and primary AML specimens, along with a notable decrease in downstream signaling pathways. Furthermore, the suppression of ROCK2 caused disruption of cellular energy production pathways by directly affecting the functionality of proteins within the mitochondrial electron transport chain. Finally, we discovered that TRIM26, a specific E3 ligase, is capable of ubiquitylating ROCK2, and the upregulation of TRIM26 within HL-60/ADM cells resulted in heightened sensitivity to the drug and reduced resistance. Thus, our study presents a new strategy for overcoming drug resistance in AML through targeting ROCK2/AKT/MAPK signaling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Comprehensive characterization of AML-associated T cells during disease progression is essential to identify relevant immune escape mechanisms and new immunotherapeutic approaches. Investigating the processes that lead to an immunosuppressive environment under progression of AML is difficult in humans, because by the time of diagnosis the disease is often progressed far beyond the initial stages. Therefore, to investigate T-cell phenotypes during progression a C57BL/6 mouse model was used. The CD3 + T cells were characterized by performing multiparametric flow analyses at different time points (day 0 = healthy mice, day 7, day 14, and day 21). The study revealed that the spleen is highly infiltrated by reg CD4 + T cells at day 21 of AML progression. These spleen-infiltrating reg CD4 + T cells mainly showed an effector memory differentiation with high expression and co-expression of the checkpoint molecules TIGIT, PD-1, OX40, and the two ectoenzymes CD39 and CD73. Substantial expression of the checkpoint molecules was restricted to the central memory and effector memory compartments. Furthermore, functional evaluation of TIGIT was performed. Blocking TIGIT resulted in a significantly increased lysis of C1498 AML cells in cocultures with AML-primed CD3 + T cells. Together these data confirm that the expression of the checkpoint receptor TIGIT is relevant for dysfunction of AML-associated T cells and, thus, represents a suitable target for future immunotherapeutic approaches.

Acute myeloid leukemia (AML) is a deadly hematopoietic malignancy. Although many patients achieve complete remission with standard induction therapy, a combination of cytarabine and anthracycline, ~40% of patients have induction failure. These refractory patients pose a treatment challenge, as they do not respond to salvage therapy or allogeneic stem cell transplant. Herein, we show that AML patients who experience induction failure have elevated expression of the NF-κB target gene tumor necrosis factor alpha-induced protein-3 (TNFAIP3/A20) and impaired necroptotic cell death. A20 High AML are resistant to anthracyclines, while A20 Low AML are sensitive. Loss of A20 in AML restores sensitivity to anthracycline treatment by inducing necroptosis. Moreover, A20 prevents necroptosis in AML by targeting the necroptosis effector RIPK1, and anthracycline-induced necroptosis is abrogated in A20 High AML. These findings suggest that NF-κB-driven A20 overexpression plays a role in failed chemotherapy induction and highlights the potential of targeting an alternative cell death pathway in AML., (© 2024. The Author(s).)

Endothelial cells are integral components of all vasculature within complex organisms. As they line the blood vessel wall, endothelial cells are constantly exposed to a variety of molecular factors and shear force that can induce cellular damage and stress. However, how endothelial cells are removed or eliminate unwanted cellular contents, remains unclear. The generation of large extracellular vesicles (EVs) has emerged as a key mechanism for the removal of cellular waste from cells that are dying or stressed. Here, we used intravital microscopy of the bone marrow to directly measure the kinetics of EV formation from endothelial cells in vivo under homoeostatic and malignant conditions. These large EVs are mitochondria-rich, expose the 'eat me' signal phosphatidylserine, and can interact with immune cell populations as a potential clearance mechanism. Elevated levels of circulating EVs correlates with degradation of the bone marrow vasculature caused by acute myeloid leukaemia. Together, our study provides in vivo spatio-temporal characterization of EV formation in the murine vasculature and suggests that circulating, large endothelial cell-derived EVs can provide a snapshot of vascular damage at distal sites., (© 2024. The Author(s).)

Abstract: For several decades, induction therapy with nucleoside analogs, in particular cytarabine (Ara-C) and, to a lesser extent, fludarabine, has been the standard of care for patients diagnosed with acute myeloid leukemia (AML). However, the antitumor efficacy of nucleoside analogs is often limited by intrinsic and acquired drug resistance, thereby leading to poor therapeutic response and suboptimal clinical outcomes. In this study, we used genome-wide CRISPR-based pharmacogenomic screening to map the genetic factors that modulate the response to nucleoside analogs in AML and identified the E3 ubiquitin ligase, Herc1, as a key modulator of Ara-C response in mouse AML models driven by the KMT2A/MLLT3 fusion or by the constitutive coexpression of Hoxa9 and Meis1, both in vitro and in vivo. Loss of HERC1 enhanced nucleoside analog-induced cell death in both murine and human AML cell lines by compromising cell cycle progression. In-depth proteomic analysis and subsequent validation identified deoxycytidine kinase as a novel target of Herc1 in both mouse AML models. We observed that HERC1 is overexpressed in AML when compared with other cancer types and that higher HERC1 expression was associated with shorter overall survival in patients with AML in the The Cancer Gene Atlas program (TCGA) and BEAT-AML cohorts. Collectively, this study highlights the importance of HERC1 in the response of AML cells to nucleoside analogs, thereby establishing this E3 ubiquitin ligase as a novel predictive biomarker and potential therapeutic target for the treatment of AML., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: A long non-coding RNAs (LncRNAs) called antisense noncoding RNA in the INK4 locus ( ANRIL ), has emerged as substantial regulators of cell survival in acute myeloid leukemia (AML). However, its speciffc and potential mechanism is uncertain in AML. In this research, we investigated the role of ANRIL in cell proliferation, apoptosis, and the underlying mechanism in AML cells., Methods: ANRIL expression was quantified by real-time quantitative polymerase chain reaction (RT-qPCR). Kasumi-1 cells were transfected with LV- ANRIL plasmid to upregulate ANRIL expression, with or without co-transfection with a G Protein-Coupled Receptor Kinase 2 (GRK2) siRNA. Additionally, these cells were transfected with sh- ANRIL plasmid to inhibit ANRIL expression, with or without co-transfection with a GRK2 overexpression plasmid. Cell proliferation and apoptosis were determined using the cell counting kit-8 (CCK8) and flow cytometry. Protein expression levels of phosphatidylinositide 3-kinases (PI3K), protein kinase B (AKT), phosphorylated-Akt (p-AKT), Bcl-2-associated protein x (BAX), B-cell leukemia/lymphoma 2 protein (BCL-2), proliferating cell nuclear antigen (PCNA), cleaved caspase-3, and GRK2 were detected by western blot. The RNA-binding protein immunoprecipitation (RIP) assay was conducted to investigate the interaction between ANRIL and GRK2., Results: ANRIL expression was increased in Kasumi-1 cells. ANRIL upregulation expression promoted cell proliferation and inhibited apoptosis. Furthermore, its upregulation led to increased expressions of PI3K, AKT, p-AKT, PCNA, and BCL-2, and decreased expression of BAX in Kasumi-1 cells. Additionally, transfection with GRK2 siRNA attenuated the promoting effect of LV- ANRIL on Kasumi-1 cells proliferation and the PI3K/AKT pathway, increased BAX and cleaved caspase-3 expressions, and decreased BCL-2 and PCNA expressions. GRK2 overexpression reversed the inhibitory effect of sh- ANRIL on cell proliferation and the PI3K/AKT pathway. Furthermore, it promoted BCL-2 and PCNA expressions, and inhibited BAX and cleaved caspase-3 expressions. RIP assay confirmed the physical interaction between ANRIL and GRK2., Conclusion: The GRK2 protein-mediated ANRIL , increasing Kasumi-1 cell proliferation and inhibiting apoptosis by activating the PI3K/AKT/BCL-2 pathway., (© 2024 The Author(s). Published by IMR Press.)

Venetoclax plus azacitidine treatment is clinically beneficial for elderly and unfit acute myeloid leukemia (AML) patients. However, the treatment is rarely curative, and relapse due to resistant disease eventually emerges. Since no current clinically feasible treatments are known to be effective at the state of acquired venetoclax resistance, this is becoming a major challenge in AML treatment. Studying venetoclax-resistant AML cell lines, we observed that venetoclax induced sublethal apoptotic signaling and DNA damage even though cell survival and growth were unaffected. This effect could be due to venetoclax inducing a sublethal degree of mitochondrial outer membrane permeabilization. Based on these results, we hypothesized that the sublethal apoptotic signaling induced by venetoclax could constitute a vulnerability in venetoclax-resistant AML cells. This was supported by screens with a broad collection of drugs, where we observed a synergistic effect between venetoclax and PARP inhibition in venetoclax-resistant cells. Additionally, the venetoclax-PARP inhibitor combination prevented the acquisition of venetoclax resistance in treatment naïve AML cell lines. Furthermore, the addition of azacitidine to the venetoclax-PARP inhibitor combination enhanced venetoclax induced DNA damage and exhibited exceptional sensitivity and long-term responses in the venetoclax-resistant AML cell lines and samples from AML patients that had clinically relapsed under venetoclax-azacitidine therapy. In conclusion, we mechanistically identify a new vulnerability in acquired venetoclax-resistant AML cells and identify PARP inhibition as a potential therapeutic approach to overcome acquired venetoclax resistance in AML., (© 2024. The Author(s).)

Acute myeloid leukemia (AML) is a hematological malignancy with a high recurrence rate. The interaction of chemokine receptor 4/chemokine ligand 12 (CXCR4/CXCL12) mediates homing and adhesion of AML cells in bone marrow, leading to minimal residual disease in patients, which brings a hidden danger for future AML recurrence. Ara-C is a nonselective chemotherapeutic agent against AML. Due to its short half-life and severe side effects, a lipid-like Ara-C derivative (AraN) was synthesized and a dual-function LipoAraN-E5 (135 nm, encapsulation efficiency 99%) was developed, which coloaded AraN and E5, a peptide of the CXCR4 antagonist. LipoAraN-E5 effectively improved the uptake, enhanced the inhibition of leukemia cell proliferation, migration, and adhesion to stromal cells in bone marrow, and mobilized the leukemia cells from bone marrow to peripheral blood via interfering with the CXCR4/CXCL12 axis. LipoAraN-E5 prolonged the plasma half-life of AraN (8.31 vs 0.56 h) and was highly enriched in peripheral blood (3.67 vs 0.05 μmol/g at 8 h) and bone marrow (379 vs 148 μmol/g at 24 h). LipoAraN-E5 effectively prevented the infiltration of leukemia cells in peripheral blood, bone marrow, spleen, and liver, prolonged the mice survival, and showed outstanding antineoplastic efficacy with negligible toxicity, which were attributed to the ingenious design of AraN, the use of a liposomal delivery carrier, and the introduction of E5. Our work revealed that LipoAraN-E5 may be a promising nanocandidate against AML.

Tissue-specific differences in the expression of paralog genes, which are not essential in most cell types due to the buffering effect of the partner pair, can make for highly selective gene dependencies. To identify selective paralogous targets for acute myeloid leukemia (AML), we integrated the Cancer Dependency Map with numerous datasets characterizing protein-protein interactions, paralog relationships, and gene expression in cancer models. In this study, we identified ATP1B3 as a context-specific, paralog-related dependency in AML. ATP1B3, the β-subunit of the sodium-potassium pump (Na/K-ATP pump), interacts with the α-subunit ATP1A1 to form an essential complex for maintaining cellular homeostasis and membrane potential in all eukaryotic cells. When ATP1B3's paralog ATP1B1 is poorly expressed, elimination of ATP1B3 leads to the destabilization of the Na/K-ATP pump. ATP1B1 expression is regulated through epigenetic silencing in hematopoietic lineage cells through histone and DNA methylation in the promoter region. Loss of ATP1B3 in AML cells induced cell death in vitro and reduced leukemia burden in vivo, which could be rescued by stabilizing ATP1A1 through overexpression of ATP1B1. Thus, ATP1B3 is a potential therapeutic target for AML and other hematologic malignancies with low expression of ATP1B1. Significance: ATP1B3 is a lethal selective paralog dependency in acute myeloid leukemia that can be eliminated to destabilize the sodium-potassium pump, inducing cell death., (©2024 American Association for Cancer Research.)

Beyond its clinical diversity and severity, acute myeloid leukemia (AML) is known for its complex molecular background and for rewiring biological processes to aid disease onset and maintenance. FLT3 mutations are among the most recurring molecular entities that cooperatively drive AML, and their inhibition is a critical molecularly oriented therapeutic strategy. Despite being a promising avenue, it still faces challenges such as intrinsic and acquired drug resistance, which led us to investigate whether and how autophagy and inflammasome interact and whether this interaction could be leveraged to enhance FLT3 inhibition as a therapeutic strategy. We observed a strong and positive correlation between the expression of key genes associated with autophagy and the inflammasome. Gene set enrichment analysis of the FLT3-ITD samples and their ex vivo response to five different FLT3 inhibitors revealed a common molecular signature compatible with autophagy and inflammasome activation across all poor responders. Inflammasome activation was also shown to strongly increase the likelihood of a poor ex vivo response to the FLT3 inhibitors quizartinib and sorafenib. These findings reveal a distinct molecular pattern within FLT3-ITD AML samples that underscores the necessity for further exploration into how approaching these supportive parallel yet altered pathways could improve therapeutic strategies., (© 2024. The Author(s).)

Background: Quiescent self-renewal of leukemia stem cells (LSCs) and resistance to conventional chemotherapy are the main factors leading to relapse of acute myeloid leukemia (AML). Alpha-enolase (ENO1), a key glycolytic enzyme, has been shown to regulate embryonic stem cell differentiation and promote self-renewal and malignant phenotypes in various cancer stem cells. Here, we sought to test whether and how ENO1 influences LSCs renewal and chemoresistance within the context of AML., Methods: We analyzed single-cell RNA sequencing data from bone marrow samples of 8 relapsed/refractory AML patients and 4 healthy controls using bioinformatics and machine learning algorithms. In addition, we compared ENO1 expression levels in the AML cohort with those in 37 control subjects and conducted survival analyses to correlate ENO1 expression with clinical outcomes. Furthermore, we performed functional studies involving ENO1 knockdown and inhibition in AML cell line., Results: We used machine learning to model and infer malignant cells in AML, finding more primitive malignant cells in the non-response (NR) group. The differentiation capacity of LSCs and progenitor malignant cells exhibited an inverse correlation with glycolysis levels. Trajectory analysis indicated delayed myeloid cell differentiation in NR group, with high ENO1-expressing LSCs at the initial stages of differentiation being preserved post-treatment. Simultaneously, ENO1 and stemness-related genes were upregulated and co-expressed in malignant cells during early differentiation. ENO1 level in our AML cohort was significantly higher than the controls, with higher levels in NR compared to those in complete remission. Knockdown of ENO1 in AML cell line resulted in the activation of LSCs, promoting cell differentiation and apoptosis, and inhibited proliferation. ENO1 inhibitor can impede the proliferation of AML cells. Furthermore, survival analyses associated higher ENO1 expression with poorer outcome in AML patients., Conclusions: Our findings underscore the critical role of ENO1 as a plausible driver of LSC self-renewal, a potential target for AML target therapy and a biomarker for AML prognosis., (© 2024. The Author(s).)

Abstract: Acute myeloid leukemia (AML) with the t(7;12)(q36;p13) translocation occurs only in very young children and has a poor clinical outcome. The expected oncofusion between break point partners (motor neuron and pancreas homeobox 1 [MNX1] and ETS variant transcription factor 6 [ETV6]) has only been reported in a subset of cases. However, a universal feature is the strong transcript and protein expression of MNX1, a homeobox transcription factor that is normally not expressed in hematopoietic cells. Here, we map the translocation break points on chromosomes 7 and 12 in affected patients to a region proximal to MNX1 and either introns 1 or 2 of ETV6. The frequency of MNX1 overexpression in pediatric AML is 2.4% and occurs predominantly in t(7;12)(q36;p13) AML. Chromatin interaction assays in a t(7;12)(q36;p13) induced pluripotent stem cell line model unravel an enhancer-hijacking event that explains MNX1 overexpression in hematopoietic cells. Our data suggest that enhancer hijacking may be a more widespread consequence of translocations in which no oncofusion product was identified, including t(1;3) or t(4;12) AML., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Abstract: Inflammation promotes solid tumor progression, but how regulatory mechanisms of inflammation may affect leukemia is less well studied. Using annexin A5 (ANXA5), a calcium-binding protein known for apoptosis, which we discovered to be differentially expressed in the bone marrow microenvironment (BMM) of mice with acute myeloid (AML) vs chronic myeloid leukemia, as a model system, we unravel here a circuit in which AML-derived tumor necrosis factor α (TNF-α) dose-dependently reduces ANXA5 in the BMM. This creates an inflammatory BMM via elevated levels of prostaglandin E2 (PGE2). Via binding to its EP4 receptor, PGE2 increases β-catenin and hypoxia-inducible factor 1α signaling in AML cells, thereby accelerating PGE2-sensitive AML. Human trephine biopsies may show lower ANXA5 expression and higher PGE2 expression in AML than other hematologic malignancies. Furthermore, syngeneic and xenogeneic transplantation models suggest a survival benefit after treatment with the inhibitor of prostaglandin-endoperoxide synthase 2 (cyclooxygenase 2 [COX2]), celecoxib, plus cytarabine in those AML types highly sensitive to PGE2 compared with cytarabine alone. Taken together, TNF-α/ANXA5/NF-κB/COX2/PGE2-mediated inflammation influences AML course in a highly differential and circular manner, and patients with AML with "inflammatory AML" may benefit from antiphlogistic agents as adjunct therapy., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Acute myeloid leukemia (AML) represents a highly malignant subtype of leukemia with limited therapeutic options. In this study, we propose a novel therapeutic strategy for treating AML by inhibiting SIRT3 to regulate mitochondrial metabolism network involved in energy metabolism and epigenetic modifications essential for AML survival. A series of thieno [3,2-d]pyrimidine-6-carboxamide derivatives were designed and synthesized by structure-based strategy, 17f was documented to be a potent and acceptable selective SIRT3 inhibitor with IC 50 value of 0.043 μM and exhibited profound anti-proliferative activity in MOLM13, MV4-11, and HL-60 cells. Through CETSA assay and the degree of deacetylation of intracellular SIRT3 substrates, we confirmed that 17f could effectively bind and inhibit SIRT3 activity in AML cells. Mechanistically, 17f suppressed mitochondrial function, triggered the accumulation of ROS, and significantly inhibited the production of ATP in AML cells. With the breakdown of mitochondrial function, 17f eventually induced apoptosis of AML cells. In addition, 17f also showed excellent anti-AML potential in nude mouse tumor models of HL-60-Luc. Collectively, these results demonstrate that 17f is a potent and acceptable selective SIRT3 inhibitor with promising potential to treat AML., Competing Interests: Declaration of competing interest The author declare that they have no conflict of Interests., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL-2, creating a therapeutic opportunity to target LSCs using the BCL-2 inhibitor venetoclax. Although venetoclax-based regimens have shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence venetoclax responsiveness. Our data show that utilization of mitochondrial calcium is fundamentally different between drug-responsive and nonresponsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate an active metabolic (i.e., OXPHOS) status with relatively high levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter. We demonstrate that inhibition of calcium uptake reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in LSCs and provide an avenue for clinical management of venetoclax resistance. Significance: We identify increased utilization of mitochondrial calcium as a distinct metabolic requirement of venetoclax-resistant LSCs and demonstrate the potential of targeting mitochondrial calcium uptake as a therapeutic strategy., (©2024 American Association for Cancer Research.)

Acute myeloid leukaemia (AML) remains a major unmet medical, despite recent progress in targeted molecular therapies. One aspect of leukaemic cell resistance to chemotherapy is the development of clones with increased capacity to respond to cellular stress and the production of reactive oxygen species (ROS), thanks in particular to a high aldehyde dehydrogenases (ALDH) 1A1/2 activity. At diagnosis, ROS level and ALDH1A1/2 activity in AML patients BM are correlated with the different ELN 2022 prognostic groups and overall survival (OS). A significant lower ALDH1A1/2 activity in BM was observed in the favourable ELN2022 subgroup compared to the intermediate and adverse group (p < 0.01). In the same way, the ROS levels were significantly lower in the favourable ELN 2022 subgroup compared to the intermediate group (p < 0.0001) and adverse group (p < 0.0002). ROS high AML patients had a significantly lower median overall survival (OS) (8.2 months) than ROS low patients (24.6 months) (p = 0.0368). After first-line therapy, a significant increase of ROS level (p = 0.015) and ALDH1A1/2 activity (0 = 0.0273) in leukaemic blasts was observed, especially in the refractory ones. ABD-3001, a competitive and irreversible inhibitor of ALDHs 1 and 3, can in vitro inhibit the proliferation of patient-derived leukaemic cells in accordance with redox balance. In multivariate analysis, ROS level was the most significant (p < 0.05) and the strongest predictive factor for the sensitivity of cells to ABD-3001. The safety profile of ABD-3001 is currently being assessed through the first inhuman multicenter phase 1 clinical trial "ODYSSEY" (NCT05601726) for patients with relapsed AML., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Acute myeloid leukaemia (AML) is a bone marrow malignancy with poor prognosis. One of several treatments for AML is midostaurin combined with intensive chemotherapy (MIC), currently approved for FLT3 mutation-positive (FLT3-MP) AML. However, many patients carrying FLT3 mutations are refractory or experience an early relapse following MIC treatment, and might benefit more from receiving a different treatment. Development of a stratification method that outperforms FLT3 mutational status in predicting MIC response would thus benefit a large number of patients., Methods: We employed mass spectrometry phosphoproteomics to analyse 71 diagnosis samples of 47 patients with FLT3-MP AML who subsequently received MIC. We then used machine learning to identify biomarkers of response to MIC, and validated the resulting predictive model in two independent validation cohorts (n = 20)., Findings: We identified three distinct phosphoproteomic AML subtypes amongst long-term survivors. The subtypes showed similar duration of MIC response, but different modulation of AML-implicated pathways, and exhibited distinct, highly-predictive biomarkers of MIC response. Using these biomarkers, we built a phosphoproteomics-based predictive model of MIC response, which we called MPhos. When applied to two retrospective real-world patient test cohorts (n = 20), MPhos predicted MIC response with 83% sensitivity and 100% specificity (log-rank p < 7∗10 -5 , HR = 0.005 [95% CI: 0-0.31])., Interpretation: In validation, MPhos outperformed the currently-used FLT3-based stratification method. Our findings have the potential to transform clinical decision-making, and highlight the important role that phosphoproteomics is destined to play in precision oncology., Funding: This work was funded by Innovate UK grants (application numbers: 22217 and 10054602) and by Kinomica Ltd., Competing Interests: Declaration of interests WEB—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences, named on a Kinomica patent; LN—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; SFP—is an employee at Kinomica, owns Kinomica share options; AEC—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; NN—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; JAC—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; DNP—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; PMC—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; JK—is an employee at Kinomica, owns Kinomica share options; HRF—no conflict of interest; BP—no conflict of interest; PG—no conflict of interest; AA—no conflict of interest; AJA—received a honorarium for speaking engagements from Astellas; AT—received consultant fees from Kinomica for the role of Programme Director; AW—owns Kinomica share options, funded attendance and travel to conferences; GG—no conflict of interest; MDM—no conflict of interest; JGG—Kinomica co-founder, owns Kinomica share options; DJB—co-founder of Kinomica, owns Kinomica share options, named on Kinomica patents, Kinomica funded attendance and travel to conferences, received honoraria from Kinomica in a consulting role; PRC—co-founder and director of Kinomica, owns Kinomica share options, named on Kinomica patents, Kinomica funded attendance and travel to conferences, received honoraria from Kinomica in a consulting role; ADD—is an employee at Kinomica (CTO), named on Kinomica patents, Kinomica funded attendance and travel to conferences owns Kinomica share options., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Alternative splicing is an efficient and ubiquitous transcriptional regulatory mechanism that expands the coding capacity of the genome and is associated with the occurrence and progression of cancer. The differentiation-promoting regimen is a potential therapeutic approach in cancer treatment. In this study, we screened NPMc-positive and NPMc-negative acute myeloid leukemia (AML) samples from the Cancer Genome Atlas, focusing on the splicing factor RNA-binding motif protein 4 (RBM4) and its splicing mechanism on the target gene transcription factor EB (TFEB), which are most relevant to the prognosis of AML. We also investigated the impact of the TFEB-dominant spliceosome on autophagy and differentiation of THP-1 and K562 cells. The results showed that RBM4 recognized the CU-rich sequence in intron 8 of TFEB, increasing the production of the TFEB-L spliceosome, which promoted autophagy. Overexpression of RBM4 increased autophagy and promoted cell differentiation. The combination of TFEB-L with the therapeutic drug rapamycin further promoted the differentiation of leukemia cell lines and primary leukemia cells in AML patients. This study suggested that overexpression of RBM4 could promote cell differentiation by promoting the production of the TFEB-dominant spliceosome, demonstrating the potential of the TFEB-dominant spliceosome combined with chemotherapy drugs to promote leukemia cell differentiation and improve patient prognosis., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Small extracellular vesicles (sEV) transfer cargos between cells and participate in various physiological and pathological processes through their autocrine and paracrine effects. However, the pathological mechanisms employed by sEV-encapsulated microRNA (miRNA) in acute myeloid leukemia (AML) are still obscure. In this study, we aimed to investigate the effects of AML cell-derived sEV (AML-sEV) on AML cells and delineate the underlying mechanisms. We initially used high-throughput sequencing to identify miR-221-3p as the miRNA prominently enriched in AML-sEV. Our findings revealed that miR-221-3p promoted AML cell proliferation and leukemogenesis by accelerating cell cycle entry and inhibiting apoptosis. Furthermore, Gbp2 was confirmed as a target gene of miR-221-3p by dual luciferase reporter assays and rescue experiments. Additionally, AML-sEV impaired the clonogenicity, particularly the erythroid differentiation ability, of hematopoietic stem and progenitor cells. Taken together, our findings reveal how sEV-delivered miRNA contribute to AML pathogenesis, which can be exploited as a potential therapeutic target to attenuate AML progression.

Exosomes are bilayer lipid bodies and contain a variety of bioactive molecules such as proteins, lipids, and nucleic acids, and so forth. Exosomes derived from solid tumors may play critical roles in tumor development and immune evasion. However, the underlying effects of tumor-derived exosomes on immune function in modulating intercellular crosstalk within the bone marrow niche during acute myeloid leukemia (AML) development and immune evasion remain largely elusive. In this study, we aimed to explore the role of AML-exos in AML immune evasion. First, we isolated tumor-derived exosomes from AML cells (AML-exos) and revealed the presence of programmed cell death ligand-1 (PD-L1) protein in AML-exos. Next, we demonstrated that AML-exos can directly suppress the activation of natural killer (NK) cells and inhibit the cytotoxicity of NK cells, probably through activating the programmed cell death-1 (PD-1)/PD-L1 pathway. Furthermore, the inhibitory effect of AML-exos on NK cells could be alleviated by either PD-L1 inhibitor or antagonist. In summary, we demonstrated that AML-exos possess a PD-L1-dependent tumor-promoting effect which may contribute to immune tolerance in antitumor therapy, but blocking the PD-1/PD-L1 pathway may alleviate the tumor immunosuppression induced by AML-exos. Our findings in this study may offer a new immunotherapy strategy to cure AML., (© 2024 International Federation for Cell Biology.)

Even though acute myeloid leukemia (AML) patients with a RUNX1::RUNX1T1 (AE) fusion have a relatively favorable prognosis, approximately 50% relapse within 2.5 years and develop resistance to subsequent chemotherapy [1]. It is therefore imperative to identify novel therapeutic targets for AE leukemia to improve outcomes. In this study, we unveil that targeting STING effectively suppresses the growth of AE leukemia cells. Both genetic and pharmacological inhibition of STING lead to the diminish of AE leukemia cells. Importantly, in a mouse primary AE leukemia model, STING deletion significantly attenuates leukemogenesis and prolongs the animals' lifespan. Blocking the downstream inflammatory pathway of STING yields similar effects to STING inhibition in AE leukemia cells, highlighting the pivotal role of STING-dependent inflammatory responses in sustaining the survival of AE leukemia cells. Moreover, through a genome-wide CRISPR screen, we identified fatty acid desaturase 2 (FADS2) as a non-canonical factor downstream of STING inhibition that mediates cell death. Inhibition of STING releases FADS2 activity, consequently inducing the synthesis of polyunsaturated fatty acids (PUFAs) and triggering lipid peroxidation-associated cell death [2]. Taken together, these findings reveal a critical function of STING in the survival of AE-positive AML cells and suggest STING to be a potential therapeutic target for clinical intervention in these patients., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: The purpose of this study was to investigate the effects and potential mechanisms of ferroptosis-related gene heat shock protein beta-1 (HSPB1) on acute myeloid leukemia (AML)., Methods: The RNA-seq and clinical data of AML samples were obtained from the Genomic Data Commons database, and the FerrDb database was used to screen the marker, drive and suppressor of ferroptosis. Besides, DESeq2 was applied for differential expression analysis on AML samples and screening for differentially expressed genes (DEGs). The screened DEGs were subjected to the intersection analysis with ferroptosis-related genes to identify the ferroptosis-related DEGs. Next, the functional pathways of ferroptosis-related DEGs were further be discussed by Gene Ontology as well as Kyoto Encyclopedia of Genes and Genomes enrichment analysis of DEGs. Additionally, lasso regression analysis was employed to determine the differential genes related to prognosis in patients with AML and the survival analysis was performed. Subsequently, quantitative real-time polymerase chain reaction and western blot assay were applied to detect the mRNA and protein expression levels of HSPB1 in normal/AML bone marrow tissues and human normal (HS-5)/AML (HL-60) bone marrow cells, respectively. Furthermore, HSPB1 was knocked down to assess the expression changes of glutathione peroxidase 4 and acyl-CoA synthetase long-chain family member 4. Ultimately, the viability and oxidative stress levels of HL-60 were analyzed by Cell Counting Kit-8 and biochemical detection., Results: A total of 4986 DEGs were identified in AML samples, with 3324 up-regulated and 1662 down-regulated. The enrichment analysis illustrated that ferroptosis-related DEGs were significantly enriched in response to metal irons, oxidative stress, and other pathways. After lasso regression analysis, 17 feature genes related to the prognosis of patients with AML were obtained, with HSPB1 exhibiting a significant correlation. The reliability of our models was verified by Cox regression analysis and survival analysis of the hazard model. Furthermore, the outcomes of quantitative real-time polymerase chain reaction and western blot showed that mRNA and protein expression levels of HSPB1 were significantly increased in the AML Group and HL-60 cells. The knockdown of HSPB1 in HL-60 cells reduced the protein level of glutathione peroxidase 4, increased the protein level of acyl-CoA synthetase long-chain family member 4, decreased the cell viability, and aggravated oxidative stress., Conclusion: Ferroptosis-related gene HSPB1 is highly expressed in patients with AML. In addition, HSPB1 may be involved in the occurrence and development of AML by regulating oxidative stress and ferroptosis-related pathways. This study provides new clues for further understanding of AML molecular mechanisms. Also, HSPB1 is expected to be a potential therapeutic target for AML in the future., (© 2024 John Wiley & Sons Ltd.)

Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are common hematological malignancies in adults. Despite considerable research advances, the development of standard therapies, supportive care, and prognosis for the majority of AML and ALL patients remains poor and the development of new effective therapy is urgently needed. Here, it is reported that activation of thermogenic adipose tissues (TATs) by cold exposure or β3-adrenergic receptor agonists markedly alleviated the development and progression of AML and ALL in mouse leukemia models. TAT activation (TATA) monotherapy substantially reduces leukemic cells in bone marrow and peripheral blood, and suppresses leukemic cell invasion, including hepatomegaly and splenomegaly. Notably, TATA therapy prolongs the survivals of AML- and ALL-bearing mice. Surgical removal of thermogenic brown adipose tissue (BAT) or genetic deletion of uncoupling protein 1 (UCP1) largely abolishes the TATA-mediated anti-leukemia effects. Metabolomic pathway analysis demonstrates that glycolytic metabolism, which is essential for anabolic leukemic cell growth, is severely impaired in TATA-treated leukemic cells. Moreover, a combination of TATA therapy with chemotherapy produces enhanced anti-leukemic effects and reduces chemotoxicity. These data provide a new TATA-based therapeutic paradigm for the effective treatment of AML, ALL, and likely other types of hematological malignancies., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)