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Renal angiomyolipoma (AML) is a rare benign tumor of the kidney, often detected incidentally on radiological images as the presence of macroscopic fat characterizes them. In the majority of the cases, they are usually sporadic. Despite their benign nature, venous invasion, a rare occurrence in renal AMLs, poses management challenges. We present a case of bilateral renal AML in a 52-year-old female with a right renal vein and hepatic inferior vena cava invasion.

Additional cytogenetic abnormalities (ACA) are known to crop up in Ph+ cells of chronic myeloid leukemia (CML) patients due to cytogenetic evolution. But the frequency of molecular evolution and ACA is much less in Ph− cells of CML patients and is poorly understood. We report an interesting and rare case of Ph+ CML, who progressed to B lymphoblastic crisis, achieved remission, and later developed Ph− acute myeloid leukemia (AML) with KMT2A gene rearrangement and no detectable BCR- ABL transcripts.

Objective: Human granulocyte colony-stimulating factor (G-CSF) plays a vital role in boosting neutrophil production from hematopoietic progenitor cells, both in lab settings and within the human body. Beyond just raising neutrophil counts, G-CSF primes these cells, enhancing their ability to defend the body, making it a key player not only for neutropenic patients but also for those who are immunocompromised but not necessarily neutropenic. G-CSF is widely used in treating acute myeloid leukemia (AML), either alongside or following chemotherapy. One of its primary benefits is to speed up neutrophil recovery after chemotherapy, reducing both the length of hospital stays and the risk of infection.Here, we share a case involving a 17-year-old male with AML who developed pleural effusion after receiving G-CSF during his cytotoxic treatment. Case Report: The patient, a 17-year-old male, came to our clinic with an elevated white blood cell count and was subsequently diagnosed with acute myeloid leukemia (AML) after a bone marrow aspiration. He was immediately started on the 7+3 induction chemotherapy protocol. During the post-chemotherapy phase, when his neutrophil levels dropped, filgrastim (G-CSF) was introduced to help reduce the risk of infection and shorten the neutropenic period. For the first five days, everything seemed normal, and no side effects were noted. However, after that initial period, the patient began to experience worsening shortness of breath. Imaging revealed a growing pleural effusion on the left side. A diagnostic thoracentesis was performed, and the fluid was drained to provide relief. The analysis confirmed the fluid was transudative, with no signs of infection or malignancy. When the pleural effusion returned, G-CSF was promptly stopped, and the effusion rapidly resolved. After consolidation therapy, G-CSF was reintroduced, and once again, pleural effusion reappeared on the third day of treatment, but this too resolved spontaneously once the G-CSF was discontinued. A pleural biopsy showed no pathological findings, confirming that the G-CSF was likely responsible for the effusion. Discussion: In neutropenic patients, pleural effusion is typically linked to infections, but in this case, no signs of infection or AML involvement were found. The recurring pleural effusion, which resolved after stopping G-CSF, suggests a rare side effect of the treatment. Research indicates that G-CSF may trigger local inflammatory responses, including elevated cytokines like IL-6 and TNF-α, potentially leading to fluid accumulation in the pleura. This case highlights the importance of monitoring for unusual side effects during G-CSF therapy in AML patients.

Background: Acute myeloid leukemia (AML) has been identified as a top priority for discovering a reliable biomarker for treatment improvement and patient outcome prediction due to the heterogeneous nature of AML and the obstacle to find an appropriate treatment strategy for this malignancy. Considering the involvement of long noncoding RNA (lncRNA) SNHG7 and BGL3 found in various cancers, the exact expression pattern of these lncRNAs and their clinical implications in acute myeloid leukemia (AML) continue to be elusive. In order to demonstrate a possible mechanism underlying AML pathogenesis, our goal was to examine BGL3 and SNHG7 lncRNA expressions in PI3K pathway. Methods: This case-control cross-sectional study were conducted on RNA extracted from blood samples of 30 patients diagnosed with AML (Ayatollah-Khansari hospital, Arak, Iran) and 30 (age and gender matched) healthy controls. The expression levels of SNHG7 and BGL3 lncRNAs and their target genes Akt and PTEN, were measured using qRT-PCR. Subsequently, by means of statistical analysis, we determined the plausible correlation between the expressions of the aforementioned genes and lncRNA respectively. Results: In AML samples, a considerable increase in the expression levels of SNHG7 lncRNA and Akr gene was accompanied by a marked reduction in the expression levels of BGL3 lncRNA and PTEN gene. Nevertheless, No significant relationship between the expression level of the indicated genes/lncRNAs and age and sex was found. The remarkable correlation between the expression of genes/lncRNAs and the blast percentage in patients was the notable point in the result of this study. Conclusions: As the most straightforward interpretation of our results, we propose that perhaps the association between SNHG7 and BGL3 built through the interaction between Akt and PTEN may play a crucial role in the AML pathogenesis and any element of this axis could be a potential novel target for further profound treatment strategies. Nonetheless, in the context of Hematological Malignancies, particularly AML, more detailed studies are needed in this area to elucidate the precise role played by this interesting testis-specific pathway.

Introduction: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative approach in patients with relapsed and high-risk leukemia. This retrospective analysis aimed to investigate outcomes and risk factors associated with HSCT in children and young adults with hematological malignancies in a resource-limited setting. Methods: We retrospectively evaluated 48 pediatric and young adult patients diagnosed with hematological malignancies who underwent HSCT at our institution between April 2017 and Jan 2023. Result: The median age of the cohort was 10 years (6 months - 21 years), and the majority of patients underwent transplants for acute lymphoblastic leukemia (ALL) (n = 24; 50 %) and acute myeloid leukemia (n = 18; 37.5%). Median time to neutrophil and platelet engraftment were 15 days (range 9–28) and 18 days (range 9–40), respectively. One patient had primary graft failure. Cytomegalovirus reactivation occurred in 21 patients (43.8%). Seventeen patients received escalated donor lymphocyte infusion (DLI). With a median follow-up of 902 days (52–2490), the probability of event free survival and overall survival (OS) was 65.9% and 69.4%. OS for lymphoid and myeloid malignancies were 64.7% and 75.2%, respectively. Kaplan-Meier probabilities of OS for patients in first complete remission (CR), CR2, CR3, or with refractory disease were 80%, 76.2%, 0%, and 40%, respectively (p = 0.02). OS of the patients undergoing matched sibling donor (n = 17) or haploidentical HSCT (n = 31) was 70.6% and 69%, respectively (p = 0.989). Conclusions: Our study demonstrates excellent outcomes of patients with hematological malignancies undergoing allogeneic HSCT with similar outcomes in HLA-identical sibling donors and haploidentical first-degree family donors. Prophylactic DLI might be considered in patients with high-risk leukemia to prevent relapse, including ALL.

Current CD33-targeted immunotherapies typically recognize the membrane-distal V-set domain of CD33. Here, we show that decreasing the distance between T cell and leukemia cell membrane increases the efficacy of CD33 chimeric antigen receptor (CAR) T cells. We therefore generated and optimized second-generation CAR constructs containing single-chain variable fragments from antibodies raised against the membrane-proximal C2-set domain, which bind CD33 regardless of whether the V-set domain is present (CD33PAN antibodies). CD33PAN CAR T cells resulted in efficient tumor clearance and improved survival of immunodeficient mice bearing human AML cell xenografts and, in an AML model with limited CD33 expression, forced escape of CD33neg leukemia. Compared to CD33V-set CAR T cells, CD33PAN CAR T cells showed greater in vitro and in vivo efficacy against several human AML cell lines with differing levels of CD33 without increased expression of exhaustion markers. CD33PAN moieties were detected at a higher frequency on human leukemic stem cells, and CD33PAN CAR T cells had greater in vitro efficacy against primary human AML cells. Together, our studies demonstrate improved efficacy with CAR T cells binding CD33 close to the cell membrane, providing the rationale to investigate CD33PAN CAR T cells further toward possible clinical application.

AML is a malignant tumor derived from the hematopoietic system, which has a poor prognosis and its incidence is increasing recent years. LncRNAs bind to miRNAs as competitive endogenous RNAs to regulate the occurrence and progression of AML， with IL-6R playing a crucial role in hematological malignancies. However, the mechanism by which noncoding RNAs regulate IL6R expression in AML remains unclear. This study found that the AC010247.2/miR-125b-5p axis promotes AML progression by regulating IL-6R expression. Specifically, knocking down or inhibiting AC010247.2 and miR-125b-5p affected IL6R and its downstream genes. Mechanistically, AC010247.2 acts as a ceRNA for miR-125b-5p, influencing IL-6R expression. Additionally, AC010247.2's regulation of AML progression partially depends on miR-125b-5p. Notably, the AC010247.2/miR-125b-5p/IL6R axis serves as a better polygenic diagnostic marker for AML. Our study identifies a key ceRNA regulatory axis that modulates IL6R expression in AML, providing a reliable multigene diagnostic method and potential therapeutic target.

Background: Several transcription factors and co-factors are encoded by the RFX (Regulatory Factor X) family (RFX1-8) and associated genes (RFXAP and RFXANK). Increasing evidence suggests that the RFX family and associated genes are involved in the development and progression of cancer. However, no prior research has focused on a multi-omic analysis of these genes to evaluate their role in tumor progression. Methods: Using combined TCGA and GTEx pan-cancer data, we investigated the expression patterns and survival profiles of these ten genes. We then focused on RFX8 to analyze its clinicopathological and therapeutic features. Finally, we conducted experimental validation of RFX8 function in acute myeloid leukemia (AML). Results: RFX5 and RFXANK showed higher expression levels, while RFX6 showed lower expression levels in most types of cancer, with RFX8 being the most upregulated in LAML. RFX2 and RFXAP demonstrated prognostic significance in eight types of cancer, and RFX8 showed significance in six types of cancer. The expression of these ten genes exhibited specific characteristics in immune subtypes, tumor microenvironment, and stemness. The expression of RFX8 was correlated with various tumor stages, microsatellite instability (MSI), tumor mutation burden (TMB), immune cell infiltration, and immune-checkpoint expression. Additionally, RFX8 was found to regulate tumorigenesis and sensitivity to chelerythrine in AML. Conclusions: Our work delineated the landscape of the RFX family and associated genes in the pan-cancer context and the specific role of RFX8 in AML. These findings might offer cues for further investigations of these genes in cancer biology.

Background: India's need for bone marrow donation and transplantation is increasing in the context of the rising incidence of haematological neoplasms like acute myeloid leukaemia (AML). The use of matched related donors (MRD) for hematopoietic stem cell transplantation (HSCT) is a feasible option, but the lack of HLA-matched donors in India remains a significant obstacle to successful treatment. Methodology: This retrospective study was conducted at the Department of Hemato-Oncology & Bone Marrow Transplant, Rajiv Gandhi Cancer Institute in New Delhi, India over a period of 6 months. The study enrolled 77 AML MRD and 19 AML MUD patients based on the inclusion and exclusion criteria. Result: The one-year survival rate was higher in MRD than in MUD, but there was no significant difference in mortality in multivariate analysis. The study also found that chronic graft-versus-host disease (GVHD) and relapse were associated with worse survival outcomes in both MRD and MUD HSCT. Conclusion: This study supports the use of matched unrelated donor (MUD) transplant for HSCT in AML patients when a matched sibling donor is not available.

CRISPR-based screens have discovered novel functional genes involving in diverse tumor biology and elucidated the mechanisms of the cancer pathological states. Recently, with its randomness and unbiasedness, CRISPR screens have been used to discover effector genes with previously unknown roles for AML. Those novel targets are related to AML survival resembled cellular pathways mediating epigenetics, synthetic lethality, transcriptional regulation, mitochondrial and energy metabolism. Other genes that are crucial for pharmaceutical targeting and drug resistance have also been identified. With the rapid development of novel strategies, such as barcodes and multiplexed mosaic CRISPR perturbation, more potential therapeutic targets and mechanism in AML will be discovered. In this review, we present an overview of recent progresses in the development of CRISPR-based screens for the mechanism and target identification in AML and discuss the challenges and possible solutions in this rapidly growing field.

Ras-related C3 botulinum toxin substrate 1 (Rac1) is a GTPase implicated in cell migration and homing of hematopoietic cells to the hematopoietic niche, and is commonly overexpressed in acute myeloid leukemia (AML). This can lead to quiescence of leukemic blasts in the niche and reduced response to therapy. We investigated the Rac1 inhibitor EHop-016 on AML by assessing its effects on MOLM-13 cells in vitro and in zebrafish larvae, regarding cell motility and therapeutic potential in combination with daunorubicin (DNR). In vitro assessment of proliferation and viability was by measurement of 3H-thymidine incorporation and detection of Annexin V/PI positive cells. Cell motility was evaluated by measurement of migration in a transwell system. Fluorescently stained MOLM-13 cells were injected into zebrafish larvae, and individual cells followed by confocal microscopy. Cell accumulation in the caudal hematopoietic tissue (CHT) was studied using a 12-hour timelapse, while in vivo efficacy of DNR, EHop-016 or a combination was investigated over 24 h.The in vitro results showed that EHop-016 acted synergistically in combination with DNR in reducing the viability of MOLM-13 cells (Bliss synergy score above 10 %). Non-toxic concentrations of EHop-016 reduced cell migration. These findings were reproduced in zebrafish larvae: larvae receiving both DNR and EHop-016 had significantly reduced tumor burden compared to the untreated control or single treatments. The accumulation of MOLM-13 cells in the CHT was reduced in larvae receiving EHop-016 treatment.Our findings demonstrate that targeting Rac1 in AML holds promise as a complementary treatment to established chemotherapy and should be further investigated.

Upper-extremity mucormycosis is a rare, life-threatening fungal infection mainly affecting immunocompromised patients. We report a case of a 30-year-old woman with acute myelogenous leukemia who developed this infection during her hospital stay. The culprit was Mucorales, a subgroup of Zygomycetes species known for fast-progressing, highly lethal infections. She presented with fever, chills, and a lesion on her left forearm that worsened despite initial broad-spectrum antibiotics. A punch biopsy confirmed the diagnosis, leading to antifungal therapy with isavuconazonium sulfate and later amphotericin B, combined with surgery. Timely intervention is critical because delayed treatment can result in severe complications and death. Early suspicion, histology, microscopy, and fungal cultures are vital for accurate diagnosis. Treatment primarily involves amphotericin B, whereas adjunctive therapies such as topical amphotericin B and hyperbaric oxygen show promise. This case underscores the importance of prompt medical and surgical action, enhancing early detection of mucormycosis in immunocompromised patients.

Acute myeloid leukemia (AML) is a common blood cancer primarily affecting the bone marrow and blood cells, which is prevalent among adults. Long non-coding RNAs (lncRNAs) have been shown to play a crucial role in the development and progression of AML. LBX2-AS1 is a recently discovered lncRNA that has been linked to the pathogenesis and progression of several types of cancer. This study aimed to investigate the role and possible mechanisms of LBX2-AS1 in AML. Expression levels of LBX2-AS1, miR-455-5p, and their target genes were detected in AML samples and cells by RT-qPCR. Cell proliferation and apoptosis were determined by Cell Counting Kit-8 and 5-ethynyl-2′-deoxyuridine assays, and flow cytometry, respectively. LBX2-AS1 was downregulated in AML specimens and cells, and overexpression of LBX2-AS1 significantly inhibited cell proliferation and enhanced apoptosis in vitro. We also determined the effects of LBX2-AS1 overexpression in an AML mouse model by in vivo bioluminescence imaging. Mechanistically, LBX2-AS1 acts as a competitive endogenous RNA, which promotes myosin regulatory light chain interacting protein (MYLIP) expression by sponging miR-455-5p. Knockdown of MYLIP or upregulation of miR-455-5p antagonized the effect of LBX2-AS1 overexpression on the progression of AML. LBX2-AS1 may thus be a valuable therapeutic target for AML.

A 63-year-old woman presented with plaques covering 60 % body-surface-area and leonine facies. Blood work showed no diagnostic aberrancies. Skin biopsy contained a malignant CD4+/CD56+ mononuclear cell population concerning for blastic plasmacytoid dendritic cell neoplasm. A later bone marrow biopsy confirmed AML with KMT2A::MLLT10 fusion detected by next-generation sequencing (NGS). This patient's LC preceded blood and marrow based symptoms of AML. NGS of the initial skin biopsy should be considered as part of diagnostic guidelines in cases with LC in the differential as this may have led to earlier diagnosis in this case and future cases.

Mixed-phenotype acute leukemia (MPAL) is a rare form of leukemia with ambiguous lineage, and there are challenges in accurately diagnosing this entity according to formal criteria. Here we report a case which was initially diagnosed as “AML” based on atypical peripheral blood flow cytometry that was subsequently determined to be B-ALL with KMT2A rearrangement based on marrow results. Although KMT2A rearrangements represent a defining genetic abnormality for acute leukemia of ambiguous lineage, this case did not meet the criteria for MPAL based on WHO 2022 criteria. This case highlights the diagnostic challenges of MPAL and the potential limitations of the current classification. We discuss the most appropriate workup and management of these patients and identify areas for future study.

Acute myeloid leukemia (AML) patients undergoing induction chemotherapy receive transfusion support to manage severe cytopenias and associated sequelae. Jehovah's Witness (JW) patients typically decline transfusion of most or all blood products. This can lead to exclusion of JW patients from otherwise life-saving treatments due to safety concerns. We present two cases demonstrating the successful induction of JW patients without the need for red cell or platelet transfusion support; the first, an older AML patient induced with azacitidine & venetoclax; the second, a patient with acute promyelocytic leukemia induced using arsenic trioxide and all-trans retinoic acid. Both patients required modifications to the induction regimens to accommodate their wishes. These cases support growing evidence that selected JW patients with AML can be successfully treated using appropriate accommodations.

CD33 and CD123 are expressed on the surface of human acute myeloid leukemia blasts and other noncancerous tissues such as hematopoietic stem cells. On-target off-tumor toxicities may limit chimeric antigen receptor T cell therapies that target both CD33 and CD123. To overcome this limitation, we developed bispecific human CD33/CD123 chimeric antigen receptor (CAR) T cells with an “AND” logic gate. We produced novel CD33 and CD123 scFvs from monoclonal antibodies that bound CD33 and CD123 and activated T cells. Screening of CD33 and CD123 CAR T cells for cytotoxicity, cytokine production, and proliferation was performed, and we selected scFvs for CD33/CD123 bispecific CARs. The bispecific CARs split 4-1BB co-stimulation on one scFv and CD3ζ on the other. In vitro testing of cytokine secretion and cytotoxicity resulted in selecting bispecific CAR 1 construct for in vivo analysis. The CD33/CD123 bispecific CAR T cells were able to control acute myeloid leukemia (AML) in a xenograft AML mouse model similar to monospecific CD33 and CD123 CAR T cells while showing no on-target off-tumor effects. Based on our findings, human CD33/CD123 bispecific CAR T cells are a promising cell-based approach to prevent AML and support clinical investigation.

There is growing evidence of a strong association between SARS-CoV-2 and cancer prognosis and treatment outcome. However, there are no reliable SARS-CoV-2 assessment models to accurately predict prognostic and therapeutic effects in acute myeloid leukemia (AML). Here, differentially expressed genes associated with SARS-CoV-2 were detected, and multiple Cox regression methods were used to construct a SARS-CoV-2 risk index (SC2RI). Then, RT-qPCR was used to validate the gene expression levels in the AML samples. Finally, we explored how the SC2RI affected prognosis, immune infiltration, immunotherapy, and drug sensitivity in AML. We found that CYB5R3 and CLIP4 had been confirmed as hub genes in AML and were used to generate the SC2RI. The datasets indicated that the SC2RI had a superior predictive impact on the prognosis of AML. In addition, high expression of immune checkpoints and numerous immunological infiltrations were substantially correlated with a high SC2RI. However, it responded poorly to immune checkpoint blockade, which may be related to T-cell dysfunction, lack of effective antigens, and deficiency of synaptic capacity. Moreover, a high SC2RI was less susceptible to mTOR-related pathway medications but more sensitive to cell cycle suppressors. Therefore, categorization based on SC2RI could enhance the prognostic prediction of AML and help identify novel therapeutic approaches.

Acute myeloid leukemia (AML) is a hematological malignancy that contains hereditary subgroups. AML can arise as a result of a previous myeloid malignancy. AML's molecular pathogenesis is not yet complete. NADPH quinone dehydrogenase 1 (NQ01), which is linked to AML, is one of a few handfuls of genes that have a role in AML pathogenesis. The goal of this study was to look at the roles of C609T and C465T polymorphisms in the NQ01 gene in the development of AML in Saudis. In this experimental study, 100 AML patients and 100 healthy controls were chosen. For the C609T and C465T PCR products, restriction enzymes were utilized in this study. AML cases and controls were investigated for genotype and allele frequencies. The average age of AML patients and control subjects was 39.9 ± 12.06 years. AML patients were 61% male and 39% female, while controls were 54% male and 46% female. The C609T and C465T polymorphisms in the NQ01 gene were not linked with any of the genotypes (p > 0.05). According to the findings of this investigation, the C609T and C465T polymorphisms play no effect in AML patients in Saudi Arabia.

The development of epithelial-to-mesenchymal transition (EMT) like features is emerging as a critical factor involved in the pathogenesis of acute myeloid leukaemia (AML). However, the extracellular signals and the signalling pathways in AML that may regulate EMT remain largely unstudied. We found that the bone marrow (BM) mesenchymal/fibroblastic cell line HS5 induces an EMT-like migratory phenotype in AML cells. AML cells underwent a strong increase of vimentin (VIM) levels that was not mirrored to the same extent by changes of expression of the other EMT core proteins SNAI1 and SNAI2. We validated these particular pattern of co-expression of core-EMT markers in AML cells by performing an in silico analysis using datasets of human tumours. Our data showed that in AML the expression levels of VIM does not completely correlate with the co-expression of core EMT markers observed in epithelial tumours. We also found that vs epithelial tumours, AML cells display a distinct patterns of co-expression of VIM and the actin binding and adhesion regulatory proteins that regulate F-actin dynamics and integrin-mediated adhesions involved in the invasive migration in cells undergoing EMT. We conclude that the BM stroma induces an EMT related pattern of migration in AML cells in a process involving a distinctive regulation of EMT markers and of regulators of cell adhesion and actin dynamics that should be further investigated. Understanding the tumour specific signalling pathways associated with the EMT process may contribute to the development of new tailored therapies for AML as well as in different types of cancers.

Mutations in the plant homeodomain-like finger protein 6 (PHF6) gene are strongly associated with acute myeloid (AML) and T-cell acute lymphoblastic leukemia (T-ALL). In this study, we demonstrated that PHF6 can bind to H3K9me3 and H3K27me1 on the nucleolar chromatin and recruit histone methyltransferase SUV39H1 to the rDNA locus. The deletion of PHF6 caused a decrease in the recruitment of SUV39H1 to rDNA gene loci, resulting in a reduction in the level of H3K9me3 and the promotion of rDNA transcription. The knockdown of either SUV39H1 or PHF6 significantly attenuated the effects of increase in H3K9me3 and suppressed the transcription of rDNA induced by the overexpression of the other interacting partner, thereby establishing an interdependent relationship between PHF6 and SUV39H1 in their control of rRNA transcription. The PHF6 clinical mutants significantly impaired the ability to bind and recruit SUV39H1 to the rDNA loci, resulting in an increase in rDNA transcription activity, the proliferation of in vitro leukemia cells, and the growth of in vivo mouse xenografts. Importantly, significantly elevated levels of pre-rRNA were observed in clinical AML patients who possessed a mutated version of PHF6. The specific rDNA transcription inhibitor CX5461 significantly reduced the resistance of U937 AML cells deficient in PHF6 to cytarabine, the drug that is most commonly used to treat AML. Collectively, we revealed a novel molecular mechanism by which PHF6 recruits methyltransferase SUV39H1 to the nucleolar region in leukemia and provided a potential therapeutic target for PHF6-mutant leukemia.

Patients with NPM1 gene mutation-associated acute myeloid leukemia (AML), particularly those over the age of 60, have no viable targeted therapeutic choices. In this study, we identified HEN-463, a sesquiterpene lactone derivative specific targets AML with this gene mutation. This compound inhibits the interaction of LAS1-NOL9 by covalently binding to the C264 site of the ribosomal biogenesis-related protein LAS1, which translocates the LAS1 to the cytoplasm, thereby inhibiting the maturation of 28 S rRNA. This has a profound effect on the NPM1-MDM2-p53 pathway and ultimately results in the stabilization of p53. Combining this treatment with the XPO1 inhibitor Selinexor (Sel) can ideally preserve the stabilized p53 in the nucleus, considerably enhancing the efficacy of HEN-463 and addressing Sel's drug resistance. Patients with AML over the age of 60 who possess the NPM1 mutation have an unusually elevated level of LAS1, which has a significant impact on their prognosis. In NPM1-mutant AML cells, decreased LAS1 expression promotes proliferation inhibition, apoptosis, cell differentiation, and cell cycle arrest. This suggests that it may be a therapeutic target for this kind of blood cancer, especially in patients over the age of 60.

Objective: To illustrate patterns of cytogenetic abnormalities that promote progression and/or transformation in myelodysplastic syndrome., Methods: In this study we evaluated three different data sets to identify recurrent cytogenetic abnormalities (RCAs) to delineate the cytogenetic evolutionary trajectories and their clinical significance., Results: Datasets 1 and 2 were 2402 cross sectional samples from Mitelman database of Chromosome Aberrations and Gene Fusions in Cancer; these were used to discover RCAs and to validate them. Dataset 3 was a cohort of 163 institutional patients with serial samples from 35 % of them. This was used to further validate RCAs identified in the cross-sectional data, and their clinical impact. We identified MDS subtype associated RCAs, and some exclusive RCAs (Xp-, 2q-, 17q-, 21q-) that led to disease progression or transformation to leukemia. Evolutionary pathway analysis had shown temporal acquisition of RCAs. Therefore, presence of two or more RCAs suggests cooperative or complementary role in disease progression or transformation. Patients with one or more of these RCAs had poor prognosis and high risk for transformation. Genes frequently altered in MDS are mapped to some of the RCAs and suggest a close correlation between RCAs and molecular alterations in MDS. Karyotypic complexity, clonal evolution, loss of 17p had poor clinical outcomes., Conclusion: This study identified a unique combination of RCAs that are components in distinct cytogenetic trajectories. Some of these were primary changes while others were secondary or tertiary changes. Acquiring specific additional aberrations predicts progression or transformation to leukemia., Competing Interests: Declaration of competing interest Authors (García, Alkayyali, Mosquera Gomez, Wright, Chen, Oliver and Koduru) declare there are no known competing financial or personal interests that influence the work documented in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Older/unfit adults with AML have worse outcomes and fewer treatment options than their younger/fit counterparts. In vitro studies have found a synergistic effect of hypomethylating agents (HMA) with venetoclax (VEN) on AML cells and since the phase 3 VIALE-A trial demonstrated a survival benefit, HMA + VEN has become the standard of care in the frontline setting for older/unfit adults with AML. Unfortunately, the standard 28-day cycle of VEN is associated with a high degree of myelosuppression leading to treatment delays and dose modifications. Many small retrospective studies have successfully shown comparable outcomes to VIALE-A with reduced dose/duration of VEN. Furthermore, low dose metronomic dosing of HMA + VEN has shown clinical benefit while minimizing myelotoxicity. Future trials are vital to understand the appropriate dose of VEN in combination with HMA, to evaluate HMA + VEN compared to intensive therapy for younger/fit patients, and to explore its utility in the relapsed/refractory setting., Competing Interests: Declaration of competing interest Hannah Levavi receives consulting fees from Sobi. Keith Pratz receives research funding from AbbVie, Agios, Daiichi Sankyo, Millennium; advisory board member for AbbVie, Astellas, AstraZeneca, Boston Biomedical, Bristol Myers Squibb, Celgene, Novartis, Roche, Jazz Pharmaceuticals, and Servier. Douglas Tremblay receives contracted research funding paid to his institution from Sobi, Sumitomo, Cogent Biosciences and Gilead and consulting fees from Sobi, Novartis, AbbVie, Pharmaessentia, Sierra Oncology, GSK and Cogent Biosciences. All other authors have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: FLT3-ITD AML is associated with an increased risk of relapse, leading many patients to receive an allogeneic hematopoietic stem cell transplantation (alloHCT) after induction. Unfortunately, relapse rate after alloHCT remains high and strategies are needed to improve outcomes., Materials and Methods: We performed a retrospective analysis of adult patients with FLT3-ITD AML who received alloHCT from 6/1/2016 to 12/31/2020 and received gilteritinib (GILT) or sorafenib (SORA)as post-transplant maintenance, outside of a clinical trial., Results: A total of 55 patients were treated with either GILT (n = 27) or SORA (n = 29) for post-HCT maintenance. One patient was treated with SORA after first alloHCT and GILT after second alloHCT. Patient characteristics were comparable between groups. FLT3 inhibitors were utilized in pre-alloHCT therapy in all but 1 patient. The median duration of time that patients remained on GILT was 385 days (range, 10-804) and on SORA 315 days (range, 3-1777). 1-year PFS and relapse incidence were similar between GILT and SORA; PFS was 66% versus 76% (P = .4) and relapse incidence was 19% versus 24% (P = .6), respectively.Both groups had high incidence of Grade 3-4 hematological toxicity, including neutropenia (45% GILT and 34% SORA) and thrombocytopenia (30% GILT and 52% SORA). Only 44% and 14% patients who received GILT and SORA did not discontinue maintenance, respectively., Conclusion: Our results revealed comparable PFS and a similar toxicity profile when SORA and GILT are used as post- HCT maintenance therapy., (Copyright © 2024. Published by Elsevier Inc.)

The 5th edition of the World Health Organization (WHO) classification of Hematolymphoid tumors provides a hierarchically-driven catalog of hematologic neoplasms and introduces a series of changes to the classification of acute myeloid leukemia (AML). Emphasizing molecular genetic findings, it expands the category of "acute myeloid leukemias with defining genetic abnormalities" while retaining the morphologically defined category of AML for cases that do not harbor disease-defining genetic drivers. The updates to the classification of AML provide refined definitions and diagnostic criteria based on clinicopathologic parameters and molecular genetic findings, emphasizing therapeutically and/or prognostically actionable biomarkers. This review provides an overview of the WHO 5th classification for AML with practical considerations for applying this classification system., Competing Interests: Disclosure S.L.: consultant/advisory: Guidepoint, QualWorld, Gerson Lehrman Group, Abbvie, Daiichi Sankyo, BluePrint Medicine, Caris Diagnostics, Recordat, VJ HemeOnc; AlphaSight, Arima; honorarium/speaking: OncLive, PeerView, MD Education, VJ HemeOnc, NCCN, MashUp Media, Binay Foundation, American Society of Hematology (ASH)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background Aims: Hu8F4 is a T-cell receptor-like antibody with high affinity for the leukemia-associated antigen PR1/HLA-A2 epitope. Adapted into a chimeric antigen receptor (CAR) format, Hu8F4-CAR is composed of the Hu8F4 single-chain variable fragment, the human IgG1 CH2CH3 extracellular spacer domain, a human CD28 costimulatory domain and the human CD3ζ signaling domain. We have demonstrated high efficacy of Hu8F4-CAR-T cells against PR1/HLA-A2-expressing cell lines and leukemic blasts from patients with acute myeloid leukemia in vitro. Previous studies have shown that modification of the Fc domains of IgG4 CH2CH3 spacer regions can eliminate activation-induced cell death and off-target killing mediated by mouse Fc gamma receptor-expressing cells., Methods: We generated Hu8F4-CAR(PQ) with mutated Fc receptor binding sites on the CH2 domain of Hu8F4-CAR to prevent unwanted interactions with Fc gamma receptor-expressing cells in vivo., Results: The primary human T cells transduced with Hu8F4-CAR(PQ) can specifically lyse HLA-A2 + PR1-expressing leukemia cell lines in vitro. Furthermore, both adult donor-derived and cord blood-derived Hu8F4-CAR(PQ)-T cells are active and can eliminate U937 leukemia cells in NSG mice., Conclusions: Herein, we demonstrate that modification of the IgG1-based spacer can eliminate Fc receptor binding-induced adverse effects and Hu8F4-CAR(PQ)-T cells can kill leukemia in vivo., Competing Interests: Declaration of competing interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Although monosomal karyotype (MK) has been recognized as an adverse risk factor in adult acute myeloid leukemia (AML), its impact on pediatric AML outcomes remains unclear. Methods: Clinical characteristics, cytogenetic and molecular profiling, and prognostic impact of MK were analyzed in a cohort of 284 children with AML in a Chinese population. Results: MK was present in 14 (4.5%) cases of the study cohort. MK-AML showed low prevalence of TP53 mutant and 17p13 aberrations. Children with MK-AML had shorter overall survival (OS) and event-free survival (EFS) compared to those with intermediate-risk features (OS: 26 ± 9.7% vs. 2 ± 1.5%, p

Acute Myeloid leukemia (AML) is the most common leukemia among adult population which begins with the bone marrow, but it frequently spreads to the blood stream as well. One of the common polymorphisms in AML is A66G in Methionine Synthase Reductase (MTRR), which converts isoleucine into methionine residue in the protein chain, the methionine/homocysteine cycle is disrupted. Limited studies were documented between A66G polymorphism in MTRR gene with AML. This study aimed to investigate the A66G polymorphism in MTRR gene with AML patients in the Saudi population. Peripheral blood was collected from 100 AML patients and 100 controls and DNA was isolated. Using A66G primers, polymerase chain reaction was performed followed by restriction fragment length polymorphism analysis. The mean age of both cases and controls was found to be an average of 39 years. Allele (G vs A: OR-3.41 [95 %CI: 1.87–11.24; p = 0.0001) and genotype analysis (GG vs AA: OR-3.43 [95 %CI: 1.45–8.11]; p = 0.0004) has shown the association. In conclusion, A66G polymorphism has a strong genetic role in the AML patients in Saudi population.

Gordonia is a rarely reported organism causing central line-associated bloodstream infection (CLABSI). This article reports an acute myeloid leukemia (AML) case in which the patient developed febrile neutropenia and was later found to have Gordonia bronchialis (G. bronchialis) CLABSI. The patient received a two-week ceftriaxone regimen, based on susceptibility. The microbiologic diagnosis of this organism is considered challenging due to its resemblance with other organisms; however, more sophisticated methods of diagnosis (such as gene sequencing) can aid in differentiation.

CEBPA variants are frequently recurring in acute myeloid leukemia (AML). The prognostic significance of CEBPA mutations has recently undergone a major shift in the 5th edition of WHO classification of hematological neoplasms and ELN 2022 classification. Whereas prior iterations did not specify the type of CEBPA mutation, the updated schema specify that only mutations localized to the C-terminal basic zipper (bZIP) domain are considered prognostically favorable. This change is based primarily on three recently published large datasets evaluating the prognostic significance of mutation location in CEBPA mutant AML. Here, we review the evolution of the prognostic classification of CEBPA variants.

Introduction: Flow cytometry has become an increasingly important tool in the clinical laboratory for the diagnosis and monitoring of many hematopoietic neoplasms. This method is ideal for immunophenotypic identification of cellular subpopulations in complex samples, such as bone marrow and peripheral blood. In general, 4-color panels appear to be adequate, depending on the assay. In acute leukemias (ALs), it is necessary identify and characterize the population of abnormal cells in order to recognize the compromised lineage and classify leukemia according to the WHO criteria. Although the use of eight- to ten-color immunophenotyping panels is wellestablished, many laboratories do not have access to this technology. Objective and Method: In 2015, the Brazilian Group of Flow Cytometry (Grupo Brasileiro de Citometria de Fluxo, GBCFLUX) proposed antibody panels designed to allow the precise diagnosis and characterization of AL within available resources. As many Brazilian flow cytometry laboratories use four-color immunophenotyping, the GBCFLUX has updated that document, according to current leukemia knowledge and after a forum of discussion and validation of antibody panels. Results: Recommendations for morphological analysis of bone marrow smears and performing screening panel for lineage (s) identification of AL were maintained from the previous publication. The lineage-oriented proposed panels for B and T cell acute lymphoblastic leukemia (ALL) and for acute myeloid leukemia (AML) were constructed for an appropriate leukemia classification. Conclusion: Three levels of recommendations (i.e., mandatory, recommended, and optional) were established to enable an accurate diagnosis with some flexibility, considering local laboratory resources and patient-specific needs.

Modern therapy of acute myeloid leukemia (AML) began in 1973 with the first report of the successful combination of daunorubicin and cytarabine, which led to complete remission in approximately 45% of patients. Accurate AML diagnosis was dependent on morphology, aided initially only by cytochemistry. Unlike acute lymphoblastic leukemia (ALL), immunophenotyping offered little in the diagnosis of AML, at least during the 1970s and 1980s. The advent of reliable cytogenetics changed the entire prognostic outlook of AML. With karyotypic analysis, different groups of AML could be classified and stratified for various therapies. Unique mutational profiling was a major advance in further categorizing AML patients, aided by the immunophenotypic identification of antigenic markers on the cells. All these advances were occurring as the understanding of the importance of the tumor burden—known as minimal residual disease (MRD)—became crucial for the management of AML patients. The efficacy of MRD has rapidly progressed in the past decade, from a specificity of 10−3 with immunophenotyping to 10−4 with polymerase chain reaction (PCR), which is only appropriate for some patients with AML, and finally to 10−5 or even 10−6 cells with the extraordinary sensitivity of next-generation sequencing (NGS). All of these advances have promoted the concept of personalized medicine, which has led to the advent of targeted agents that can accurately be used for specific diagnostic subtypes. Responses can be predicted and measured accurately. Such targeted agents have now become a cornerstone in the management of AML, increasing efficacy and dramatically reducing toxicity. The focus of this review is on one of the most well-studied targeted agents in AML: the FMS-like tyrosine kinase 3 (FLT3) inhibitors, which have impacted the prognostication and therapeutics of AML. This review selectively discusses the FLT3 inhibitors in detail, as a model for the other burgeoning targeted agents that have already been approved, as well as those that are currently in development.

Acute myeloid leukemia (AML) is one of the most prevalent and acute blood cancers with a poor prognosis and low overall survival rate, especially in the elderly. Although several new AML markers and drug targets have been recently identified, the rate of long-term cancer eradication has not improved significantly due to the presence and drug resistance of AML cancer stem cells (CSCs). Here we develop a novel computational pipeline to analyze the transcriptomic profiles of AML cancer (stem) cells and identify novel candidate AML CSC markers and drug targets. In our novel pipeline we apply a top-down meta-analysis strategy to integrate The Cancer Genome Atlas data with CSC datasets to infer cell stemness features. As a result, a set of genes termed the “AML key CSC genes” along with all the available drugs/compounds that could target them were identified. Overall, our novel computational pipeline could retrieve known cancer drugs (Carfilzomib) and predicted novel drugs such as Zonisamide, Amitriptyline, and their targets amongst the top ranked drugs and drug targets for targeting AML. Additionally, the pipeline applied in this study could be used for the identification of CSC-specific markers, drivers and their respective targeting drugs in other cancer types.

Acute myeloid leukemia is a hematological disease with a poor prognosis. Blast cells that characterize the disease are generally present in the bone marrow, but they can sometimes be located in different organs. This rare event can occur at diagnosis or at relapse, together or not with bone marrow involvement, and worsens prognosis and management. Despite this, the introduction into clinical practice of newly approved drugs directed towards molecular targets and approved for acute myeloid leukemia will pave the way for new treatment approaches facing this rare disease. In this paper, we present a case of a patient with acute myeloid leukemia with extramedullary manifestations involving the cutis and responding to FLT3-directed target therapy.

Aberrant activation of the Hh pathway promotes cell proliferation and multi-drug resistance (MDR) in several cancers, including Acute Myeloid Leukemia (AML). Notably, only one Hh inhibitor, glasdegib, has been approved for AML treatment, and most patients eventually relapse, highlighting the urgent need to discover new therapeutic targets. Hh signal is transduced through the membrane of the primary cilium, a structure expressed by non-proliferating mammalian cells, whose stabilization depends on the activity of HDAC6. Here we describe a positive correlation between Hh, HDAC6, and MDR genes in a cohort of adult AML patients, human leukemic cell lines, and a zebrafish model of Hh overexpression. The hyper-activation of Hh or HDAC6 in zebrafish drove the increased proliferation of hematopoietic stem and progenitor cells (HSPCs). Interestingly, this phenotype was rescued by inhibition of HDAC6 but not of Hh. Also, in human leukemic cell lines, a reduction in vitality was obtained through HDAC6, but not Hh inhibition. Our data showed the presence of a cross-talk between Hh and HDAC6 mediated by stabilization of the primary cilium, which we detect for the first time in zebrafish HSPCs. Inhibition of HDAC6 activity alone or in combination therapy with the chemotherapeutic agent cytarabine, efficiently rescued the hematopoietic phenotype. Our results open the possibility to introduce HDAC6 as therapeutic target to reduce proliferation of leukemic blasts in AML patients.

Summary: A recurrent chromosomal translocation found in acute myeloid leukemia leads to an in-frame fusion of the transcription repressor ZMYND11 to MBTD1, a subunit of the NuA4/TIP60 histone acetyltransferase complex. To understand the abnormal molecular events that ZMYND11-MBTD1 expression can create, we perform a biochemical and functional characterization comparison to each individual fusion partner. ZMYND11-MBTD1 is stably incorporated into the endogenous NuA4/TIP60 complex, leading to its mislocalization on the body of genes normally bound by ZMYND11. This can be correlated to increased chromatin acetylation and altered gene transcription, most notably on the MYC oncogene, and alternative splicing. Importantly, ZMYND11-MBTD1 expression favors Myc-driven pluripotency during embryonic stem cell differentiation and self-renewal of hematopoietic stem/progenitor cells. Altogether, these results indicate that the ZMYND11-MBTD1 fusion functions primarily by mistargeting the NuA4/TIP60 complex to the body of genes, altering normal transcription of specific genes, likely driving oncogenesis in part through the Myc regulatory network.

Acute myeloid leukemia (AML) mesenchymal stem cells (MSCs) play an essential role in protecting leukemic cells from chemotherapeutic agents through activating a wide range of adhesion molecules and cytokines. Thus, more attention should be paid to attenuate the protection of leukemic cells by MSCs. By examining the gene expression files of MSCs from healthy donors and AML patients through high-throughput microarrays, we found that interleukin (IL)-6 was an important cytokine secreted by AML MSCs to protect leukemic cells, contributing to disease progression. Strikingly, Aurora A (AURKA) was activated by IL-6, offering a new target to interfere with leukemia. Importantly, a novel AURKA inhibitor, PW21, showed excellent AURKA kinase inhibitory activities and attenuated the interaction of leukemic cells and the microenvironment. PW21 inhibited MSC-induced cell proliferation, colony formation, and migration, and it induced cell apoptosis. Mechanically, PW21 could inhibit IL-6 secreted by MSCs. Moreover, we found that PW21 displayed a strong anti-leukemia effect on non-obese diabetic (NOD)-severe combined immunodeficiency (SCID) and murine MLL-AF9 leukemic models. PW21 significantly prolonged the survival of leukemic mice and eliminated the leukemic progenitor cells. AURKA inhibitor PW21 could provide a new approach for treatment of leukemia through blocking the protection by the leukemic microenvironment in clinical application.

Chimeric antigen receptor (CAR) T cells targeting CD123, an acute myeloid leukemia (AML) antigen, hold the promise of improving outcomes for patients with refractory/recurrent disease. We generated five lentiviral vectors encoding CD20, which may serve as a target for CAR T cell depletion, and 2nd or 3rd generation CD123-CARs since the benefit of two costimulatory domains is model dependent. Four CARs were based on the CD123-specific single-chain variable fragment (scFv) 26292 (292) and one CAR on the CD123-specific scFv 26716 (716), respectively. We designed CARs with different hinge/transmembrane (H/TM) domains and costimulatory domains, in combination with the zeta (z) signaling domain: 292.CD8aH/TM.41BBz (8.41BBz), 292.CD8aH/TM.CD28z (8.28z), 716.CD8aH/TM.CD28z (716.8.28z), 292.CD28H/TM. CD28z (28.28z), and 292.CD28H/TM.CD28.41BBz (28.28.41BBz). Transduction efficiency, expansion, phenotype, and target cell recognition of the generated CD123-CAR T cells did not significantly differ. CAR constructs were eliminated for the following reasons: (1) 8.41BBz CARs induced significant baseline signaling, (2) 716.8.28z CAR T cells had decreased anti-AML activity, and (3) CD28.41BBz CAR T cells had no improved effector function in comparison to CD28z CAR T cells. We selected the 28.28z CAR since CAR expression on the cell surface of transduced T cells was higher in comparison to 8.28z CARs. The clinical study (NCT04318678) evaluating 28.28z CAR T cells is now open for patient accrual.

Chimeric antigen receptor T cells (CAR-T) targeting CD19 or B cell maturation antigen (BCMA) are highly effective against B cell malignancies. However, application of CAR-T to less differentially expressed targets remains a challenge due to lack of tumor-specific antigens and CAR-T controllability. CD123, a highly promising leukemia target, is expressed not only by leukemic and leukemia-initiating cells, but also by myeloid, hematopoietic progenitor, and certain endothelial cells. Thus, CAR-T lacking fine-tuned control mechanisms pose a high toxicity risk. To extend the CAR-T target landscape and widen the therapeutic window, we adapted our rapidly switchable universal CAR-T platform (UniCAR) to target CD123. UniCAR-T efficiently eradicated CD123+ leukemia in vitro and in vivo. Activation, cytolytic response, and cytokine release were strictly dependent on the presence of the CD123-specific targeting module (TM123) with comparable efficacy to CD123-specific CAR-T in vitro. We further demonstrated a pre-clinical proof of concept for the safety-switch mechanism using a hematotoxicity mouse model wherein TM123-redirected UniCAR-T showed reversible toxicity toward hematopoietic cells compared to CD123 CAR-T. In conclusion, UniCAR-T maintain full anti-leukemic efficacy, while ensuring rapid controllability to improve safety and versatility of CD123-directed immunotherapy. The safety and efficacy of UniCAR-T in combination with TM123 will now be assessed in a phase I clinical trial (ClinicalTrials.gov: NCT04230265).

Tyrosine kinase inhibitors (TKIs) are established drugs in the therapy of FLT3-ITD mutated acute myeloid leukemia (AML). However, acquired mutations, such as D835 in the tyrosine kinase domain (FLT3-ITD/D835), can induce resistance to TKIs. A cap analysis gene expression (CAGE) technology revealed that the gene expression of BCL2A1 transcription start sites was increased in primary AML cells bearing FLT3-ITD/D835 compared to FLT3-ITD. Overexpression of BCL2A1 attenuated the sensitivity to quizartinib, a type II TKI, and venetoclax, a selective BCL2 inhibitor, in AML cell lines. However, a type I TKI, gilteritinib, inhibited the expression of BCL2A1 through inactivation of STAT5 and alleviated TKI resistance of FLT3-ITD/D835. The combination of gilteritinib and venetoclax showed synergistic effects in the FLT3-ITD/D835 positive AML cells. The promoter region of BCL2A1 contains a BRD4 binding site. Thus, the blockade of BRD4 with a BET inhibitor (CPI-0610) downregulated BCL2A1 in FLT3-mutated AML cells and extended profound suppression of FLT3-ITD/D835 mutant cells. Therefore, we propose that BCL2A1 has the potential to be a novel therapeutic target in treating FLT3-ITD/D835 mutated AML.

We present the case of a 68 year old female who initially presented as an acute subdural hematoma but was found on further evaluation and biopsy to have subdural CNS myeloid sarcoma, without any underlying myelogenous disorder. CNS myeloid sarcoma is rare but even more so without the presence of hematologic disease, with very few cases reported in the literature for adult patients. In our review, this is the oldest patient in the literature to present with subdural myeloid sarcoma without hematologic disease. This case highlights the importance of thorough diagnostic work up and broad differentials even in seemingly routine cases with seemingly simple diagnoses.

In this study, novel substituted 1,3,5-triazine candidates (4a-d, 5a-j, and 6a-d) were designed as second-generation small molecules to act as dual IDH1 and IDH2 inhibitors according to the pharmacophoric features of both vorasidenib and enasidenib. Compounds 6a and 6b for leukemia cell lines showed from low to sub-micromolar GI 50. Moreover, compounds 4c, 5f, and 6b described the frontier antitumor activity against THP1 and Kasumi Leukemia cancer cells with IC 50 values of (10 and 12), (10.5 and 7), and (6.2 and 5.9) µg/mL, which were superior to those of cisplatin (25 and 28) µg/mL, respectively. Interestingly, compounds 4c, 6b, and 6d represented the best dual IDH1(R132H)/IDH2(R140Q) inhibitory potentials with IC 50 values of (0.72 and 1.22), (0.12 and 0.93), and (0.50 and 1.28) µg/mL, respectively, compared to vorasidenib (0.02 and 0.08) µg/mL and enasidenib (0.33 and 1.80) µg/mL. Furthermore, the most active candidate (6b) has very promising inhibitory potentials towards HIF-1α, VEGF, and SDH, besides, a marked increase of ROS was observed as well. Besides, compound 6b induced the upregulation of P53, BAX, Caspases 3, 6, 8, and 9 proteins by 3.70, 1.99, 2.06, 1.73, 1.75, and 1.85-fold changes, respectively, and the downregulation for the BCL-2 protein by 0.55-fold change compared to the control. Besides, the in vivo behavior of compound 6b as an antitumor agent was evaluated in female mice bearing solid Ehrlich carcinoma tumors. Notably, compound 6b administration resulted in a prominent decrease in the weight and volume of the tumors, accompanied by improvements in biochemical, hematological, and histological parameters., 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 Inc. All rights reserved.)

Summary: Acute myeloid leukemia (AML) is a genetically heterogeneous and frequently fatal malignancy. The ten-eleven translocation (TET)-mediated DNA demethylation is known to be critically associated with AML pathogenesis. Through chemical compound screening, we find that the opioid receptor agonist, loperamide hydrochloride (OPA1), significantly suppresses AML cell viability. The potential therapeutic effects of opioid receptor agonists, especially OPA1, are verified in AML cells in vitro and mouse and human AML models in vivo. OPA1-induced activation of OPRM1 signaling enhances the transcription of TET2 and thus activates both catalytic-dependent and -independent functions of TET2. Notably, AMLs with TET2 mutations or chemotherapy resistance are sensitive to OPA1 as well. Our results reveal the OPRM1-TET2 regulatory axis in AML and suggest that opioid agonists, particularly OPA1, a US Food and Drug Administration (FDA)-approved antidiarrheal drug, have therapeutic potential in AML, especially in TET2-mutated and chemotherapy-resistant AMLs, which have a poor prognosis.

The persistence of leukemia stem cells (LSCs) is one of the leading causes of chemoresistance in acute myeloid leukemia (AML). To explore the factors important in LSC-mediated resistance, we use mass spectrometry to screen the factors related to LSC chemoresistance and defined IFN-γ-inducible lysosomal thiol reductase (GILT) as a candidate. We found that the GILT expression was upregulated in chemoresistant CD34+ AML cells. Loss of function studies demonstrated that silencing of GILT in AML cells sensitized them to Ara-C treatment both in vitro and in vivo. Further mechanistic findings revealed that the ROS-mediated mitochondrial damage plays a pivotal role in inducing apoptosis of GILT-inhibited AML cells after Ara-C treatment. The inactivation of PI3K/Akt/ nuclear factor erythroid 2-related factor 2 (NRF2) pathway, causing reduced generation of antioxidants such as SOD2 and leading to a shifted ratio of GSH/GSSG to the oxidized form, contributed to the over-physiological oxidative status in the absence of GILT. The prognostic value of GILT was also validated in AML patients. Taken together, our work demonstrated that the inhibition of GILT increases AML chemo-sensitivity through elevating ROS level and induce oxidative mitochondrial damage-mediated apoptosis, and inhibition of the PI3K/Akt/NRF2 pathway enhances the intracellular oxidative state by disrupting redox homeostasis, providing a potentially effective way to overcome chemoresistance of AML.

Chromosomal translocation serves as a crucial diagnostic marker in the classification of acute myeloid leukemia. Among the most prevalent cytogenetic abnormalities is t(8;21)(q22;q22), typically associated with the FAB subtype AML-M2. On occasion, alternative forms of t(8;21) have been observed. This report presents a case of AML with RUNX1::RUNX1T1, wherein the karyotype revealed t(2;2;21;8)(p21;q37;q22;q22), representing the first instance of a variant t(8;21) involving both chromosomes 2. The combination of routine karyotype analysis and fluorescence in situ hybridization proves to be an effective method for identifying complex translocations of t(8;21)., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Acute myeloid leukemia (AML) is a hematologic malignancy with a high recurrence rate and poor long-term prognosis. DNA excision repair systems, such as base excision repair (BER) and nucleotide excision repair (NER), play a major role in maintaining genomic stability and integrity. Further intensive investigations are necessary to uncover additional AML prognosis loci. In this study, we analyzed 16 candidate SNPs within NER and BER pathways in AML patients. Our results showed the GT/GG genotype of the XPC rs2228001 polymorphism was significantly associated with WBC count in dominant models (OR = 0.41, 95 % CI = 0.18-0.96, p = 0.039). Additionally, the rs25487 and rs3213245 SNPs in the XRCC1 gene, in both co-dominant and dominant models, were significantly associated with PLT count in AML (p < 0.05). The GG genotype of rs1130409 in APEX1 was more prone to adverse cytogenetics in both the codominant and recessive models (p < 0.05). Furthermore, the GA genotypes of ERCC8 rs158572 in codominant model was significantly correlated with refractory group (p < 0.05). ERCC8 rs158572 and XRCC1 rs3213245 in both codominant and dominant models were significantly correlated with the MRD positivity (p < 0.05). Kaplan-Meier analysis revealed an link between overall survival (OS) and the co-dominant, dominant, and recessive models of rs2228001 in XPC. Additionally, patients with the GG and GT/GG genotype in the co-dominant, dominant model and recessive model in XPC rs2228001 exhibited significantly longer survival (p < 0.05). Multivariate Cox analyses indicated that rs2228001 in both co-dominant and dominant models were independent favorable factors impacting patient OS (OR < 1). Our findings suggest that genetic polymorphisms in DNA excision repair pathway genetic polymorphisms contribute to the chemosensitivity and prognosis of acute myeloid leukemia., 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.)