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Fms-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in acute myeloid leukemia (AML). Modern targeting of FLT3 with inhibitors has improved clinical outcomes and FLT3 inhibitors have been incorporated into the treatment of AML in all phases of the disease, including the upfront, relapsed/refractory and maintenance settings. This review will discuss the current understanding of FLT3 biology, the clinical use of FLT3 inhibitors, resistance mechanisms and emerging combination treatment strategies.

Activating mutations within FLT3 make up 30 % of all newly diagnosed acute myeloid leukemia (AML) cases, with the most common mutation being an internal tandem duplication (FLT3-ITD) in the juxtamembrane region (25 %). Currently, two generations of FLT3 kinase inhibitors have been developed, with three inhibitors clinically approved. However, treatment of FLT3-ITD mutated AML is limited due to the emergence of secondary clinical resistance, caused by multiple mechanism including on-target FLT3 secondary mutations - FLT3-ITD/D835Y and FLT3-ITD/F691L being the most common, as well as the off-target activation of alternative pathways including the BCR-ABL pathway. Through the screening of imidazo[1,2-a]pyridine derivatives, N-(3-methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine (compound 1) was identified as an inhibitor of both the FLT3-ITD and BCR-ABL pathways. Compound 1 potently inhibits clinically related leukemia cell lines driven by FLT3-ITD, FLT3-ITD/D835Y, FLT3-ITD/F691L, or BCR-ABL. Studies indicate that it mediates proapoptotic effects on cells by inhibiting FLT3 and BCR-ABL pathways, and other possible targets. Compound 1 is more potent against FLT3-ITD than BCR-ABL, and it may have other possible targets; however, compound 1 is first step for further optimization for the development of a balanced FLT3-ITD/BCR-ABL dual inhibitor for the treatment of relapsed FLT3-ITD mutated AML with multiple secondary clinical resistant subtypes such as FLT3-ITD/D835Y, FLT3-ITD/F691L, and cells co-expressing FLT3-ITD and BCR-ABL.

Background: The efficacy of a combination therapy consisting of venetoclax (VEN) and azacytidine (AZA) for newly diagnosed acute myeloid leukemia (AML) has been confirmed in elderly patients. However, the clinical data on VEN for pediatric AML are limited. A combination therapy consisting of crushed VEN tablets and AZA (VEN/AZA) was administered to two children with recurrent AML. The pharmacokinetics of VEN were then analysed. Case presentation: [Patient 1] A 1-year-old, male patient who experienced an AML relapse following an allogeneic hematopoietic stem cell transplantation received three courses of VEN/AZA. At the initial dosage of VEN (8 mg/kg), the minimum plasma concentration (Cmin) was only 0.44 µg/ml, which was far less than the optimal Cmin of 1.2 µg/ml. Subsequent dose-escalation to 10 mg/kg only achieved Cmin 0.42 µg/ml. [Patient 2] A 3-year-old, female patient in whom infantile acute lymphoblastic leukemia was originally diagnosed experienced a recurrence in the form of AML after lineage-switching. Three courses of VEN/AZA were administered with the same therapeutic drug monitoring as in Case 1. The Cmin of VEN was 0.15 µg/ml at 8 mg/kg. Afterwards, voriconazole 16 mg/kg/day was begun for a concomitant fungal infection together with VEN 2 mg/kg. This combination finally achieved Cmin 1.14 µg/ml probably through CYP3A4 inhibition by voriconazole. In terms of safety, only grade 4 hematological adverse events were observed in both patients. In terms of efficacy, patient 1 and patient 2 achieved stable disease status for two months and six months, respectively. Conclusion: Pediatric patients may scarcely achieve effective plasma concentration of VEN when crushed tablets are used at the same dosage as in adults. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy, such as chimeric antigen receptor T (CAR-T) cells targeting CD33 or CD123, has been well developed over the past decade for the treatment of acute myeloid leukemia (AML). However, the inability to sustain tumor-free survival and the possibility of relapse due to antigen loss have raised concerns. A dual targeting of CD33 and CD123 is needed for better outcomes. Methods: Based on our previously constructed CD33 and CD123 monovalent CAR-T, Loop33 × 123 and Loop123 × 33 CAR-T were constructed with molecular cloning techniques. All CAR-T cells were generated by lentivirus transduction of T cells from healthy donors. Phenotype detection was evaluated on day 7 concerning activation, exhaustion, and subtype proportions. Coculture killing assays were conducted using various AML cell lines and primary AML cells. Degranulation and cytokine secretion levels were detected by flow cytometry. Cell-derived xenograft models were established using wild-type Molm 13 cell lines, or a mixture of Molm 13-KO33 and Molm 13-KO123 cells as an ideal model of immune escape. By monitoring body weight and survival of tumor-bearing mice, Loop33 × 123 and Loop123 × 33 CAR-T cells were further assessed for their efficacy in vivo. Results: In vitro study, our results demonstrated that Loop33 × 123 CAR-T cells could efficiently eliminate AML cell lines and primary AML cells with elevated degranulation and cytokine secretion levels. Compared with our previously constructed monovalent CD33 or CD123 CAR-T cells, Loop33 × 123 CAR-T cells showed superior advantages in an immune escape model. In vivo studies further confirmed that Loop33 × 123 CAR-T cells could effectively prolong the survival of mice without significant toxicity. However, Loop123 × 33 CAR-T cells failed to show the same effects. Furthermore, Loop33 × 123 CAR-T cells efficiently circumvented potential immune escape, a challenge where monovalent CAR-T cells failed. Conclusions: Loop33 × 123 CAR-T targeting CD33 and CD123 could efficiently eliminate AML cells and prolong survival of tumor-bearing mice, while addressing the issue of immune escape. [ABSTRACT FROM AUTHOR]

AbstractAlterations in the RAS pathway underscore the pathogenic complexity of acute myeloid leukemia (AML), yet the full spectrum, including CBL, NF1, PTPN11, KRAS, and NRAS, remains to be fully elucidated. In this retrospective study of 735 adult AML patients, the incidence of RAS pathway alterations was 32.4%, each with distinct clinical characteristics. Venetoclax combined with hypomethylating agents (VEN + HMA) did not significantly improve response rates compared to intensive chemotherapy (IC) group. In the IC group, PTPN11 mutations in the N-SH2 domain showed a trend toward poorer prognosis, though not statistically significant in multivariate analysis, while NRAS mutations correlated with improved outcomes. In the VEN + HMA group, PTPN11 mutations in the N-SH2 domain emerged as an independent adverse prognostic marker. NRAS or KRAS mutations showed no survival advantage compared to wild-type, aligning with their intermediate-risk classification in the 2024 ELN guidelines. These findings emphasize the need for treatment-specific risk stratification for RAS pathway mutations in AML. [ABSTRACT FROM AUTHOR]

Cytoplasmic proliferating cell nuclear antigen (PCNA) is highly expressed in acute myeloid leukemia (AML) cells, supporting oxidative metabolism and leukemia stem cell (LSC) growth. We report on AOH1996 (AOH), an oral compound targeting cancer-associated PCNA, which shows significant antileukemic activity. AOH inhibited growth in AML cell lines and primary CD34 + CD38 − blasts (LSC-enriched) in vitro while sparing normal hematopoietic stem cells (HSCs). In vivo, AOH-treated mice demonstrated prolonged survival compared to controls (50 vs. 35 days; p < 0.0001) with reduced LSC burden, as shown in secondary transplants (42 vs. 30 days, p < 0.0001). Mechanistically, AOH disrupted mitochondrial PCNA's binding to the OPA1 protein, enhancing OPA1's interaction with its E3 ligase, MARCH5, which led to OPA1 degradation. This process reduced mitochondrial length, fatty acid oxidation (FAO), and oxidative phosphorylation (OXPHOS), thereby inhibiting LSC expansion. The addition of venetoclax (VEN), an FDA-approved Bcl-2 inhibitor, further enhanced AOH's effects, reducing mitochondrial length, FAO, and OXPHOS while improving survival in AML models. While VEN is approved for AML, AOH is under clinical investigation for solid tumors, and our findings support its broader therapeutic potential. [ABSTRACT FROM AUTHOR]

Background: The complexity of acute myeloid leukemia (AML) is increasingly recognized through the identification of distinct subgroups, including those with an APL-like immunophenotype characterized by the absence of CD34 and HLA-DR expression, which is widely recognized as a representative immunophenotype in acute promyelocytic leukemia (APL). This study sought to understand the clinical, molecular, and prognostic differences between AML patients with and without this phenotype. Methods: This study retrospectively analysed 191 de novo non-M3 AML patients and identified 32 patients with the CD34−HLA-DR− phenotype resembling APL-like immunophenotype, considered as the experimental group. Clinical data, including complete blood count, leukemic blasts, coagulation analysis DIC score, and OS, were collected, and immunophenotypic and molecular data were compared between this group and a control group of patients without this immunophenotype. Results: Patients with the CD34−HLA-DR− immunophenotype in the AML cohort had a significantly greater risk of developing disseminated intravascular coagulation (DIC) than did patients in the control group. Additionally, a lower rate of expression of immunophenotypic clusters of differentiation (CD markers) associated with poor prognosis was observed in the CD34−HLA-DR− group. At the molecular level, an increased frequency of nucleophosmin 1 (NPM1) mutations and increased expression of the Wilms' tumor 1 (WT1) gene were noted in this subgroup. However, contrary to patients with an expected favourable prognosis, patients in the favourable risk group with the CD34−HLA-DR− immunophenotype had significantly shorter overall survival than did patients in the control group. Discussion: The findings highlight the patients exhibiting the CD34−HLA-DR− immunophenotype as a unique AML subgroup with specific clinical and molecular traits, notably a predisposition to DIC, which affecting prognosis. This finding has implications for risk stratification and potential targeted therapies for AML management. [ABSTRACT FROM AUTHOR]

Summary This pilot study evaluated CPX‐351 in adults with newly diagnosed, favourable‐intermediate risk, FLT3‐ITD‐negative AML. Twenty patients received CPX‐351 for induction, with six also receiving gemtuzumab ozogamicin (GO). The complete response rate was 95%, with 42% achieving flow‐based minimal residual disease (MRD) negativity post‐induction. The 18‐month leukaemia‐free and overall survival estimates were 80% and 95% respectively. Adding GO appeared safe without prolonged cytopenias. Subclinical cardiotoxicity was observed in 25% of patients. The study demonstrated CPX‐351's feasibility, with response and MRD‐negativity rates comparable to standard ‘7 + 3’ induction. [ABSTRACT FROM AUTHOR]

Introduction: Despite remarkable progress in Pediatric Acute Myeloid Leukemia (pAML) treatments, the relapsed disease remains difficult to treat, making it pertinent to identify novel biomarkers of prognostic/therapeutic significance. Material and methods: Bone marrow samples from 21 pAML patients were analyzed using single cell RNA sequencing, functional assays with ARMH1 knockdown and overexpression were performed in leukemia cell lines to evaluate impact on proliferation and migration, and chemotherapy sensitivity. Mitochondrial function was assessed via Seahorse assay, ARMH1 interacting proteins were studied using co-immunoprecipitation. Bulk RNA-seq was performed on ARMH1 knockdown and over expressing cell lines to evaluate the pathways and networks impacted by ARMH1. Results: Our data shows that ARMH1 , a novel cancer-associated gene, is highly expressed in the malignant blast cells of multiple pediatric hematologic malignancies, including AML, T/B-ALL, and T/B-MPAL. Notably, ARMH1 expression is significantly elevated in blast cells of patients who relapsed or have a high-risk cytogenetic profile (MLL) compared to standard-risk (RUNX1, inv (16)). ARMH1 expression is also significantly correlated with the pediatric leukemia stem cell score of 6 genes (LSC6) associated with poor outcomes. Perturbation of ARMH1 (knockdown and overexpression) in leukemia cell lines significantly impacted cell proliferation and migration. The RNA-sequencing analysis on multiple ARMH1 knockdown and overexpressing cell lines established an association with mitochondrial fatty acid synthesis and cell cycle pathways.The investigation of the mitochondrial matrix shows that pharmacological inhibition of a key enzyme in fatty acid synthesis regulation, CPT1A , resulted in ARMH1 downregulation. ARMH1 knockdown also led to a significant reduction in CPT1A and ATP production as well as Oxygen Consumption Rate. Our data indicates that downregulating ARMH1 impacts cell proliferation by reducing key cell cycle regulators such as CDCA7 and EZH2. Further, we also established that ARMH1 is a key physical interactant of EZH2 , associated with multiple cancers. Conclusion: Our findings underscore further evaluation of ARMH1 as a potential candidate for targeted therapies and stratification of aggressive pAML to improve outcomes. [ABSTRACT FROM AUTHOR]

There is a high medical need to develop new strategies for the treatment of patients with acute myeloid leukemia (AML) refractory to conventional therapy. In vitro, the combinations of the blast-modulatory response modifiers GM-CSF + Prostaglandin E1, (summarized as Kit M) have been shown to convert myeloid leukemic blasts into antigen-presenting dendritic cells of leukemic origin (DCleu) that were able to (re-)activate the innate and adaptive immune system, direct it specifically against leukemic blasts, and induce memory cells. This study aimed to investigate the immune modulatory capacity and antileukemic efficacy of Kit M in vivo. Brown Norway rats suffering from AML were treated with Kit M (twofold application). Blasts and immune cells were monitored in peripheral blood (PB) and spleen. Upon the observation of promising immune modulatory effects in the treated animals, two patients with AML refractory to multiple lines of therapy were offered treatment with Kit M on an individualized basis. Safety, as well as immunological and clinical effects, were monitored. Samples obtained from a third patient in similar clinical conditions not receiving Kit M were used as controls for immune monitoring tests. Animal experiments: Drugs were well tolerated by the treated animals. After 9 days of treatment, DCleu and memory-like T cells increased in the peripheral blood, whereas regulatory T cells, especially blasts, decreased in treated as compared to untreated control animals. Clinical courses: No severe side effects were observed. In patient 1482, PB blasts remained under the detection threshold during 27 days of treatment, thrombocytes were normalized, and (leukemia specific) immune effector cells of the adaptive and innate immune system increased up to 800-fold compared to the start of treatment. Patient 1601 responded with a 12% reduction in blasts in PB immediately after Kit M treatment. Several subtypes of (leukemia-specific) immune effector cells in PB increased up to four-fold during the 19 days of treatment. In contrast, immune-reactive cells decreased under mild chemotherapy in the PB of control patient 1511 with comparably refractory AML. Within the limitation of low numbers in both animal experiments and clinical applications, our data suggest that Kit M treatment of AML-diseased rats and patients is feasible and may induce leukemia-specific immune reactions and clinical improvement. A larger series and a prospective clinical trial will be required to confirm our observations. Beyond optimized doses and schedules of the applied compounds, the combination with other antileukemic strategies or the application of Kit M in less proliferative stages of the myeloid diseases need to be discussed. If effects are confirmed, the concept may add to the armamentarium of treatments for highly aggressive blood cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: KMT2A partial tandem duplication (PTD) involves intragenic duplications within the KMT2A gene and has been associated with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). KMT2A PTD cannot be detected by conventional karyotyping or fluorescence in situ hybridization (FISH). In this study, we used optical genome mapping (OGM) to analyze the cytogenomic alterations in 1277 hematolymphoid neoplasms and identified KMT2A PTD exclusively in patients with myeloid neoplasms, including 35 (7%) with AML, 5 (2.2%) with MDS, and 5 (7.2%) with chronic myelomonocytic leukemia (CMML). Neoplasms with KMT2A PTD frequently exhibit a normal or non-complex karyotype and consistently harbor gene mutations involving epigenetic regulators, the FLT3/RAS signaling pathway, transcription factors, and spliceosome genes. Patients with KMT2A PTD are generally resistant to conventional chemotherapy, with the exception of those with de novo AML, which demonstrates a high remission rate. Patients with KMT2A PTD positive secondary AML and MDS had a poor outcome. KMT2A partial tandem duplication (PTD) involves intragenic KMT2A duplications and has been associated with poorer prognosis. In this study, we evaluated KMT2A PTD in 1277 patients with hematological malignancies using optical genome mapping (OGM). KMT2A PTD was detected in 35 patients with acute myeloid leukemia (AML) (7%), 5 patients with myelodysplastic syndrome (MDS) (2.2%), and 5 patients with chronic myelomonocytic leukemia (CMML) (7.1%). The PTDs varied in size, region, and copy number. An Archer RNA fusion assay confirmed KMT2A PTD in all 25 patients tested: 15 spanning exons 2 to 8 and 10 spanning exons 2 to 10. Most patients exhibited a normal (n = 21) or non-complex (n = 20) karyotype. The most common chromosomal abnormalities included loss of 20q or 7q and trisomy 11/gain of 11q. All patients had gene mutations, with FLT3 ITD and DNMT3A prevalent in AML and DNMT3A and RUNX1 common in MDS and CMML. Among patients who received treatment and had at least one follow-up bone marrow evaluation, 82% of those with de novo AML achieved complete remission after initial induction chemotherapy, whereas 90% of patients with secondary or refractory/relapsed AML showed refractory or partial responses. All but one patient with MDS and CMML were refractory to therapy. We conclude that OGM is an effective tool for detecting KMT2A PTD. Neoplasms with KMT2A PTD frequently harbor gene mutations and display normal or non-complex karyotypes. Patients with KMT2A PTD are generally refractory to conventional therapy, except for de novo AML. [ABSTRACT FROM AUTHOR]

AbstractIn this multicenter phase Ib trial, we investigated the combination of CPX-351 and gemtuzumab ozogamicin (GO) in relapsed/refractory acute myeloid leukemia (AML). Cohort A received CPX-351 plus a single dose of GO, while cohort B received two doses of GO. Thirteen participants received investigational treatment. Dose-limiting toxicities (DLTs) occurred in one participant in each cohort, with manageable adverse events. No cases of hepatic sinusoidal obstructive syndrome occurred. Out of 12 evaluable participants, four achieved complete remission (CR), three of whom were negative for measurable residual disease. The median time to recovery of hematopoiesis for responders was 37 days. CPX-351 with GO was feasible with acceptable toxicity and marrow recovery kinetics. Further evaluation in a larger patient cohort is necessary to assess the efficacy of this regimen in relapsed/refractory AML. [ABSTRACT FROM AUTHOR]

To elucidate the effect of BCOR mutation (BCORmut) on clinical outcomes, we included a total of 899 consecutive AML patients in a single-center during July 2016 to December 2021. Fifty cases (5.6%) had BCOR mutations, which co-occurred with mutations of RUNX1, DNMT3A, IDH2, BCORL1, STAG2, SF3B1 and U2AF1, but were exclusive with KIT and CEBPA mutations. BCORmut was also found to be exclusive with t(8;21)(q22;q22.1) AML in all patients and MLL rearrangements in the European Leukemia Net (ELN) adverse group. In those receiving intensive chemotherapy regimens, BCORmut was associated with lower complete remission (CR) rates and worse prognosis. Subgroup analysis showed that BCORmut mainly conferred a poor prognosis in the intermediate and adverse groups of the ELN2017 risk. These results suggest that BCOR mutation is an independent prognostic parameter in AML, implying BCOR mutation as a novel marker for chemorefractory disease and inferior prognosis. [ABSTRACT FROM AUTHOR]

Leukaemia stem cells (LSCs) are major contributors to chemoresistance in acute myeloid leukaemia (AML). Identifying potential biomarkers within LSCs that can predict chemosensitivity in AML is key. This prospective study involved 20 consecutive de novo AML patients who underwent '7 + 3' induction therapy. The patients were divided into CR (n = 15) and non‐CR (n = 5) groups. Using single‐cell RNA sequencing, we examined the cellular states of bone marrow mononuclear cells from AML patients at diagnosis and identified LSC among these cells. Our results showed that in non‐CR AML patients, a significant increase in the proportion of immature cells during haematopoiesis within the AML cell populations was observed. Moreover, the expression of myeloperoxidase (MPO) (log2 fold‐change = 0.89; adjusted p < 0.0001) and thyrotropin‐releasing hormone (TRH) (log2 fold‐change = 0.65; adjusted p < 0.0001) was higher within LSCs in the CR group than in the non‐CR group. Furthermore, patients with higher expression of MPO and TRH demonstrated improved relapse‐free survival (p = 0.002 for MPO; p = 0.009 for TRH) and overall survival (p = 0.002 for MPO; p < 0.001 for TRH). The connection between MPO or TRH and chemosensitivity could be linked with the downregulation of transforming growth factor and the upregulation of interferon‐α. In conclusion, MPO and TRH in LSCs could serve as chemosensitivity biomarkers in AML. [ABSTRACT FROM AUTHOR]

Background: By 2023, COVID-19 had caused 6.8 million deaths in the United States. COVID-19 presents more severely in leukemia compared to solid tumors (OR 1.6, p<0.05). However, data on Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) are limited. We investigated the mortality in AML and MDS patients with COVID-19. Methods: Data from the 2020-2021 National Inpatient Sample was used to conduct a cross-sectional analysis. We identified AML and MDS patients with COVID-19 hospitalizations through ICD-10 codes. Analysis was done by propensity matching and multivariate regression with a p-value of ≤0.05. Results: Of 28,028 AML admissions, 336 (1.2%) were admitted for COVID-19. AML-COVID-19 cohort had a lower hospitalization risk (aOR 0.3, p=0.000) and higher mortality (21.7% vs 8.7%; aOR 1.6, p=0.023) than AML patients admitted for other causes. AML patients post-HSCT (Hematopoietic Stem Cell Transplantation) had a higher risk of COVID-19 (20.2% vs 9.8%; aOR 2.6, p=0.000) and increased mortality (19.1% vs 6.7%; aOR 4.1, p=0.000) compared to other causes. Similarly, of 28,148 MDS patients, 769 (2.7%) were admitted for COVID-19. The MDS-COVID-19 cohort had a lower hospitalization risk (aOR 0.59, p=0.000) and higher mortality (19.6% vs 6.6%; aOR 2.2, p=0.000) compared to other causes. In MDS, HSCT did not alter the risk of COVID-19 hospitalizations (3% vs 3.9%; aOR 0.9, p=0.662), but these patients had higher mortality (17.4% vs 5.1%; aOR 4.0, p=0.032). Conclusion: COVID-19 hospitalization was low in AML and MDS but carried a high mortality risk. Post-HSCT, the mortality is high, warranting research into understanding the underlying factors. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML), a malignant disorder of the hematopoietic system, arises from leukemic stem cells (LSCs) and is the most prevalent form of blood cancer in adults. This study aimed to evaluate the therapeutic potential of polydatin (PD) in AML through ex vivo and in vivo studies, respectively. This study was prompted by PD's novel role in enhancing tumor apoptosis and modulating autophagy. In vitro studies were conducted using the PD-responsive AML cell line KASUMI-1 and found that PD was able to suppress cell proliferation and induce apoptosis by regulating the autophagy pathway. Subsequently, molecular docking was employed to predict the interaction between PD and Autophagy-related protein 5 (ATG5), a key regulator in the autophagy pathway. It was observed that PD inhibited the ubiquitination of ATG5 and enhanced its protein stability, leading to an increase in ATG5 protein levels and subsequent activation of the autophagy pathway (see in Abstract Graphed). The effectiveness and safety of PD in treating AML were confirmed through in vivo experiments using a mouse transplant tumor model, yielding definitive results. Collectively, these results suggest that PD is a promising candidate for the early therapeutic intervention of AML, with a strong potential for clinical application. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) relapse in acute myeloid leukemia (AML) is rare, but prognostically extremely unfavorable and associated with very high mortality rates. Aim of our single-center study was to define risk factors for CNS relapse in patients with FLT3-mutated AML after allogeneic hematopoietic cell transplantation (HCT) and to determine the impact of pre-emptive or salvage therapy with FLT3-inhibitors (FLT3i) on occurrence of CNS relapse and overall prognosis. We analyzed 39 FLT3-mutated AML patients who were treated with intensive induction therapy and consecutively underwent HCT at our institution. We observed that the remission status before HCT was strongly associated with relapse probability. Notably, FLT3-mutated AML showed a high propensity for CNS relapse with a cumulative incidence of 50% (95% confidence interval [CI], 16–77) at 2 years in non-responders pre-HCT compared to 0% in responders (cause-specific hazard ratio, 24.5, 95% CI, 2.9-206.2; p = 0.003). This was not abrogated by pre-emptive or salvage therapy with FLT3i in first relapse. Targeted therapies prior to transplant, use of intrathecal chemoprophylaxis or closer monitoring may be considered in patients with FLT3-mutated AML with active disease prior to HCT in order to prevent CNS relapse. [ABSTRACT FROM AUTHOR]

TP53 mutations in patients with AML and MDS frequently portend a poor prognosis, related to both p53 allele status and blast count. In 2022, the ICC and WHO released updated guidelines for classifying p53-mutated AML/MDS. The characteristics of p53 mutations, their associated co-mutations, and their effects on overall survival (OS) are not known in the context of these new guidelines. A retrospective chart review was undertaken for all patients with AML or MDS and at least one TP53 mutation detected on next generation sequencing (NGS) at Yale New Haven Hospital from 2015 to 2023. All patients (N = 210) met criteria for one of the 5 diagnostic classes based on WHO and ICC guidelines. Kaplan-Meier curves with associated log-rank testing and Cox proportional hazards model quantified the effects of clinical and molecular data on survival. Multi-hit pathogenic mutations were related to poorer OS in MDS but not AML using either the WHO (p =.02) or the ICC (p =.01) diagnostic criteria. The most significant predictors of OS in the sample overall were platelet count < 50 K (HR: 2.01, 95% CI [1.47, 2.75], p <.001) and TP53 VAF ≤ 40% (HR: 0.68, 95% CI[0.50, 0.91], p =.01). Blast count ranges, complex karyotype, and p53 mutation type or location, showed no association with OS. In our cohort defined by the 2022 ICC and WHO criteria, VAF and thrombocytopenia, rather than blast count or p53 mutation features, significantly predicted OS. These results speak to each criteria's ability to identify cases of similarly aggressive disease biology and prognosis. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is characterized by uncontrolled clonal expansion and differentiation block of immature myeloid cells. Some studies have shown that leukemia stem cells (LSC) are thought to be responsible for the initiation and development of leukemia. Moreover, abnormal O-glycosylation is a key modification in the process of cancer malignancy. In this study, GALNT1 expression was significantly upregulated in LSCs, while knockdown of GALNT1 inhibited cell viability and promoted apoptosis. Importantly, GALNT1 was the direct target of miR-582-5P, and MALAT1 directly interacted with miR-582-5P. In addition, Our investigation corroborated that MALAT1 functioned as an endogenous sponge of miR-582-5P to regulate mucin1 (MUC1) expression, catalyzed by GALNT1, which modulated the activity of JAK2/STAT3 pathway. MALAT1 and MUC1 were targets of transcription factor STAT3 and were regulated by STAT3. In general, these new findings indicated that MALAT1/miR-582-5P/GALNT1 axis is involved in the progression of LSCs, illuminating the possible mechanism mediated by O-glycosylated MUC1 via JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]

Understanding the underlying mechanism of acute myeloid leukemia (AML) has led to the discovery of novel biomarkers to help predict, treat and monitor leukemia. DNA (cytosine-5)-methyltransferase 3 A (DNMT3A) is considered a prognostic and therapeutic epigenetic target in AML patients with a hotspot mutation of R882. R882 mutation is associated with impaired differentiation of Hematopoietic stem cells in the bone marrow and disease progression. The prevalence of R882 mutation varied in different ethnicities and countries, and similarly, its prognostic impact differed among numerous studies. Nevertheless, the co-occurrence of mutations in R882 with NPM1 and FLT3 has been reported more frequently and is associated with a worse prognosis. These studies also suggest diverse results regarding bone marrow transplantation response as a treatment, while chemoresistance is reached as a conclusive outcome These findings highlight the crucial need for an in-depth discussion on the significance of the R882 mutation in AML patients. Understanding its impact on leukemic transformation, prognosis, and treatment is vital for advancing clinical implications. [ABSTRACT FROM AUTHOR]

Introduction: Acute myeloid leukemia (AML) is a form of cancer originating from precursor cells within the bone marrow. Elderly patients with acute leukemia require a personalized approach, considering age, performance status, and comorbidities, to determine suitability for intensive treatment. Methods: We studied the results of intense chemotherapy in 46 elderly, fit individuals with AML at a cancer center in Romania from January 2017 to December 2023. Results: The study involved a cohort of 46 patients, including 22 men and 24 women. The research indicated that 89.1% of the patients were diagnosed with de novo acute leukemia. Most patients had an ECOG score of 0–1, with one patient scoring ≥2. HCT-CI > 4 was found in 21 patients (45.7%), while CCI > 4 was present in 38 patients (82.6%). After the induction phase, 25 patients (54.3%) achieved complete remission (CR); the relapse rate was 56.8%. Upon completion of the study, nine individuals (19.6%) were still alive. The overall survival duration ranged from 0 to 33 months, with a median survival time of 8 months (CI 5.0–11.0). Conclusions: When considering treatment options for elderly patients, the Eastern Cooperative Oncology Group (ECOG) Performance Status, as well as comorbidity indices such as the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) and the Charlson Comorbidity Index (CCI), have shown promising results in the literature, indicating their relevance in the decision-making process. [ABSTRACT FROM AUTHOR]

The simultaneous occurrence of acute myeloid leukemia (AML) and autoimmune hemolytic anemia (AIHA) is exceedingly rare, with an incidence of less than 1%. We report the case of a 50–year–old patient newly diagnosed with this uncommon combination. This case underscores the complexity and infrequency of this dual diagnosis, highlighting the diagnostic and therapeutic challenges it presents. [ABSTRACT FROM AUTHOR]

Simple Summary: Acute myeloid leukemia is a malignancy of the bone marrow that is predominantly diagnosed in older patients and has historically been difficult to treat. Over the last two decades, a greater understanding of molecular pathology has led to multiple changes in the treatment landscape, reflected in both international and Dutch treatment guidelines. In this retrospective population-based cohort study, we analyzed how changes impacted first-line therapy choices, remission rates, and the survival of patients aged 60 and older with acute myeloid leukemia. Background: Acute myeloid leukemia (AML) is a malignancy of the bone marrow with a median age at diagnosis of 70 years. AML is difficult to treat, especially in older patients, among whom outcomes have historically been poor. Over the last two decades, a greater understanding of the molecular mechanisms of the pathology has led to the development of new drugs and multiple updates to treatment guidelines. Methods: A population-based retrospective cohort study was conducted for all patients aged 60 and older who were newly diagnosed with AML (n = 370) as defined by the European Leukemia Net 2022 criteria in Friesland, a Dutch province, between 2005 and 2023. Results: In this cohort of patients with a median age of 73 years, complete bone marrow analysis to classify the AML according to ELN increased in time from 49% (2005–2011) to 86% (2022–2023). The rate of patients receiving antileukemic therapy increased over time (2005–2011: 19%; 2012–2016: 64%; 2017–2021: 75%; 2022–2023: 74%), mainly driven by the introduction of hypomethylating agents. Over these time periods, the use of intensive chemotherapy (13%, 27%, 27%, and 5%) and rates of stem cell transplantation (3%, 9%, 27%, and 14%) underwent similar development as more patients were deemed eligible for these interventions from 2012 onwards, but usage declined again after the introduction of venetoclax in 2022. The median overall survival was 3.7, 7.3, 8.0, and 9.4 months over the four time periods, respectively. Conclusions: Our study demonstrates how outcomes of patients with newly diagnosed AML aged 60 and older improved over the last two decades. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukemia (AML) is a heterogeneous disease, for which identifying reliable prognostic markers is critical for accurate clinical prognosis and treatment optimization. The inhibition of emopamil-binding protein gene (EBP) expression has been demonstrated to induce cancer cell death via depleting downstream sterols. Nevertheless, no comprehensive studies have been conducted specifically in tumors, including AML. Method: Herein, survival analyses were performed on the dataset obtained from The Cancer Genome Atlas (TCGA). Besides, the EBP levels were quantified using real-time qPCR in a cohort of 120 AML patients, and the value of EBP was further assessed using our clinical data. Results: Patients with high EBP expression had worse overall survival (OS) and event-free survival (EFS) than patients with low EBP expression, both in the TCGA dataset and our clinical data. Additionally, white blood cell (WBC) counts were higher in patients with high EBP expression (P = 0.032). Moreover, in patients with intermediate-risk AML, it was discovered that elevated EBP expression was linked to a worse EFS (P = 0.038). Multivariate analysis demonstrated that high EBP expression was an independent prognostic factor in AML patients and was associated with a shorter OS and EFS (OS: P = 0.041; EFS: P = 0.017). Furthermore, the data revealed that transplantation in the high-EBP group led to an improvement in survival (OS: P = 0.001; EFS: P = 0.001). The same benefit was also observed in intermediate-risk AML patients (OS: P = 0.026; EFS: P = 0.026). Conclusion: Collectively, our findings indicated that high expression of EBP in AML patients was an adverse prognostic factor, but transplantation had the otential to alleviate its negative effects. [ABSTRACT FROM AUTHOR]

We aimed to investigate the role and mechanism of LSP1 in the progression of acute myelogenous leukemia. In this study, we established shLSP1 cell line to analyze the function of LSP1 in AML. We observed high expression of LSP1 in AML patients, whereas it showed no expression in normal adults. Furthermore, we found that LSP1 expression was associated with disease prognosis. Our results indicate that LSP1 plays a crucial role in mediating proliferation and survival of leukemia cells through the KSR/ERK signaling pathway. Additionally, LSP1 promotes cell chemotaxis and homing by enhancing cell adhesion and migration. We also discovered that LSP1 confers chemotactic ability to leukemia cells in vivo. Finally, our study identified 12 genes related to LSP1 in AML, which indicated poor survival outcome in AML patients and were enriched in Ras and cell adhesion signaling pathways. Our results revealed that the overexpression of LSP1 is related to the activation of the KSR/ERK signaling pathway, as well as cell adhesion and migration in AML patients. Reducing LSP1 expression impair AML progression, suggesting that LSP1 may serve as a potential drug therapy target for more effective treatment of AML. [ABSTRACT FROM AUTHOR]

Rearrangements and overexpression of CRLF2 are hallmarks of poor outcomes in BCR::ABL1-like B-ALL, and CRLF2 overexpression is a high-risk marker in T-ALL. However, CRLF2 alterations in pediatric hematologic malignancies other than B-ALL have not been reported. In this study, we analyzed the CRLF2 overexpression, rearrangements (P2RY8::CRLF2 and IGH::CRLF2), activation (pSTAT5 and pERK), and the expression of dominant-negative IKZF1 isoforms (Ik6 and Ik8), implied in CRLF2 dysregulation, in 16 pediatric patients (AML, n = 9; T-ALL, n = 3; LBL, n = 2; HL, n = 1; cytopenia, n = 1). A high frequency of CRLF2 rearrangements and overexpression was found in the 16 patients: 28.6% (4/14) showed CRLF2 overexpression, 93.8% (15/16) were positive for CRLF2 total protein (cell-surface and/or cytoplasmic), while 62.5% (10/16) were positive for P2RY8::CRLF2 and 12.6% (2/16) for IGH::CRLF2. In addition, 43.8% (7/16) expressed Ik6 and Ik8 isoforms. However, only a few patients were positive for the surrogate markers pSTAT5 (14.3%; 2/14) and pERK (21.4%; 3/14). [ABSTRACT FROM AUTHOR]

Introduction: In recent years, the correlation between CD117 antigen and the prognosis of hematological malignancies has been demonstrated. However, there is limited literature on the clinical significance of CD117 antigen in acute promyelocytic leukemia (APL). The aim of this study was to retrospectively analyze the clinical features and prognostic significance of CD117 in APL. Methods: In this study, we retrospectively investigated the clinicopathological characteristics, outcome, and prognostic impact of negative CD117 expression (CD117−) in 169 APL patients treated with all‐trans retinoic acid (ATRA) and arsenic trioxide (ATO) containing regimen. Results: The median follow‐up period was 63.0 months. CD117− was detected in 13 APL patients (7.7%). No significant differences were found in baseline characteristics between CD117+ and CD117− subgroups. However, compared to CD117+ APL, the incidence of early death (ED) was significantly higher in CD117− APL (p = 0.023). By multivariate analysis, CD117‐ was an independent adverse prognostic factor for overall survival (OS) and progression‐free survival (PFS) (p = 0.022 and p = 0.014, respectively). Conclusions: To sum up, CD117− is associated with greater risk of ED and has the statistical power to predict inferior OS and PFS, this marker may be considered to build prognostic scores for risk‐adapted therapeutic strategies in APL management. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukemia (AML) is a challenging heterogenous hematologic malignancy characterized by suboptimal outcomes. Genetic characterization of AML enhanced the understanding of individualized patient's risk and led to the development of new therapeutic strategies. Gene expression analysis facilitates detection of new diagnostic, prognostic, and predictive biomarkers. This necessitates the expansion of diagnostic testing with higher throughput technologies, such as targeted next-generation sequencing (NGS). Objectives: To study the expression profiles of MECOM and BAALC genes in a cohort of newly diagnosed Egyptian AML patients via Oncomine Myeloid Research assay (OMA) by NGS technology in addition to studying their potential prognostic role and impact on overall survival (OS). Methods: The OMA was used to evaluate the expression levels of MECOM and BAALC genes and five control genes (FBXW2, PUM1, TRIM27, PSMB2, and EIF2B1), in twenty-four newly diagnosed AML patients by NGS technology, using RNA extracted from bone marrow aspirate (BMA) specimens. Results: Gene expression analysis of MECOM and BAALC genes revealed that MECOM overexpression was significantly associated with the presence of lymphadenopathy and the high MECOM median expression level was significantly associated with lower hemoglobin concentrations at presentation. BAALC overexpression showed significant associations with the presence of CD34, the presence of wild type NPM1 mutation, and the absence of FLT3-ITD mutations. However, BAALC underexpression was significantly associated with normal cytogenetics, while its overexpression was associated with adverse and favorable cytogenetics, with a statistically significant difference between them (p = 0.049)*. Statistically significant positive correlation was found between BAALC expression levels and postinduction BM blast percentages. Among these two genes, only high BAALC expression had significantly shorter OS in AML patients based on the log rank test (p = 0.037)*. Conclusion: BAALC expression might be a specific molecular marker used for the assessment of prognosis and OS in AML patients and might be used in the future as targeted therapy in AML, aiming to improve patient outcomes and OS. [ABSTRACT FROM AUTHOR]

Background: AML is a complex and heterogeneous disease. The KRAS gene is one of the important genes in the pathogenesis of acute myeloid leukemia (AML). Mutant RAS can promote oncogenesis via different mechanisms including oncogenic transcription, cell cycle progression, cellular survival, growth, metabolism, and cell migration. Therefore, it is important to identify the genomic landscape of AML. The aim of the study is to identify KRAS variants in AML and their association with clinic pathological criteria and possible effects on prognosis using NGS. Method: Hotspot mutations in the KRAS gene were studied using Ion S5 next-generation sequencing system. Bone marrow samples of newly diagnosed AML patients were collected to identify hotspot mutations in the KRAS gene. DNA amplicons were subjected to sequencing and were analyzed using ion torrent software. Patients were classified according to the FAB classification system. Patients are also classified according to the cytogenetic groups and the ELN risk stratification system. Results: KRAS mutations were detected in exon 2, 3, whereas no mutations in KRAS exon 1. Interestingly, Novel mutations were detected in KRAS in AML Egyptian patients. Also, there was no statistically significant association of RAS mutations with different clinical and prognostic parameters. However, KRAS mutant patients tended to have increased PB WBC counts, percentage of PB, and bone marrow blasts. Conclusion: NGS is considered a useful tool to identify KRAS variants that could be useful for risk stratification and tailored therapy in AML patients [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a common hematologic malignancy in adults. Recent studies investigating the potential pathogenesis of AML have significantly advanced our understanding of this disease. While cytogenetics and molecular abnormalities are crucial for confirming chemotherapy response and long-term outcomes, there are additional potential therapeutic targets and prognostic factors. The CAPN1 gene, which encodes a large subunit of the ubiquitous enzyme calpain, has not been extensively studied in hematological diseases. In this study, we used data from the TCGA public database to perform a bioinformatic analysis and found that CAPN1 is differentially expressed in multiple cancers and is associated with an unfavorable prognosis in AML. We employed R software and websites such as David and STRING to conduct differential analysis, GO and KEGG analysis, and explore the correlation between CAPN1 and physiological processes and key pathways. Our findings suggest that CAPN1 is significantly associated with the structure of the extracellular matrix and receptor-ligand interactions, indicating its potential role in disease progression. Additionally, we used CYBERSORT and ssGSEA to analyze the immune environment of CAPN1 and found that it is associated with most immune components, particularly CD56 cells and neutrophils. In conclusion, CAPN1 is a key prognostic gene in AML that is significantly correlated with disease progression, clinical features, and immune invasion. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is caused by a defective precursor leading to malignant clonal expansion, often with FMS-like tyrosine kinase-3 receptor (FLT3) mutations, particularly internal tandem duplication (ITD), which has a poor prognosis. Quizartinib, a second-generation FLT3 inhibitor, has FDA approval for relapsed/refractory AML with FLT3/ITD mutation. It has shown promise in clinical studies since 2013 due to its excellent oral absorption and potent activity on FLT3. This review explores Quizartinib's mechanism of action, efficacy in monotherapy or combination with chemotherapy, drug interactions, adverse events, resistance mechanisms and future research directions. Tweetable Abstract Discover Quizartinib's journey in AML treatment: from its targeted FLT3 inhibition mechanism to overcoming resistance. Clinical trials show promise, but the battle against side effects continues. #Quizartinib #AML #FLT3resistance #ClinicalTrials. Plain Language Summary Acute myeloid leukemia (AML) is an aggressive blood cancer. The leading therapeutic choice for AML is typically chemotherapy regimens, but their relapse rates remain significant, and they often fall short. On the other hand, advances in targeted therapy have created new optimism for innovative treatment strategies. Around 30% of AML cases exhibit mutations in a receptor in their hematopoietic cells, the FMS-like tyrosine kinase-3 receptor (FLT3). The FLT3 plays a crucial role in regulating the growth and survival of hematopoietic cells. Mutations in this receptor can result in continuous activation, leading to uncontrolled cell growth and increased resistance to cell death. Quizartinib is a potent and highly selective inhibitor of FLT3, which leads to the blockage of transmission of signals that promote cell growth and survival. This article aims to review Quizartinib, explain its mechanism of action, discuss some possible benefits and consider its value in the context of AML treatment. Article highlights About 33% of adult AML patients have genetic mutations that cause the FLT3 receptor to be constantly active. The most prevalent type of this mutation is internal tandem duplication (ITD) and Quizartinib, as a second-generation, type 2 FLT3 inhibitor with excellent oral bioavailability, recently approved by the FDA for relapsed/refractory AML, especially those with FLT3/ITD mutation. Mechanism & pharmacokinetics of Quizartinib Quizartinib correctly inhibits FLT3 kinase activity, which, in the end, suppresses downstream signaling pathways liable for cell proliferation and survival. By blocking the growth of cancerous cells and causing apoptosis, this tailored strategy hopes to improve AML patients' prognosis throughout therapy. Dose adjustment Quizartinib is administered at a dose of 60 mg/m2/day, in combination with standard, salvage, or consolidation chemotherapy. Quizartinib does not have significant food or acid interactions. However, co-administration with a potent CYP3A inhibitor requires a dosage reduction from 60 to 30 mg daily. Efficacy in monotherapy & its function Administering daily doses of Quizartinib to patients with relapsed or refractory acute myeloid leukemia showed that Quizartinib was generally well-tolerated, with minimal adverse effects. Findings showed that both continuous or intermittent dosing regimens of Quizartinib had promise in treating patients (the continuous regimen had higher survival). Combination or comparison with chemotherapy Quizartinib is effective and safe when combined with different types of salvage chemotherapy, including Decitabine, Venetoclax, Omacetaxine Mepesuccinate, AZA, or low-dose cytarabine. Comparison studies between Quizartinib and salvage chemotherapy found that Quizartinib had a significant survival benefit compared with salvage chemotherapy. Gilteritinib showed a better survival rate and response rate than Quizartinib in combination with salvage chemotherapy, according to post hoc analysis. Adding Quizartinib to standard chemotherapy improved overall survival in newly diagnosed FLT3-ITD+ AML patients. Quizartinib was found effective in treating leukemia when used in conjunction with standard chemotherapy. A study suggested Quizartinib might be an effective strategy to help more FLT3-ITD AML patients undergo transplantation. Mechanisms of resistance to Quizartinib Secondary mutations in the FLT3 gene can potentially change the FLT3 receptor's structure and reduce its sensitivity to Quizartinib in some situations. FGF2 and CXCL12/CXCR4 stromal release are mechanisms of resistance to FLT3i. Increased FGF2 production precedes recurrence and provokes relapse via activation of the RAS-MAPK pathway. Drug efflux pumps, like P-glycoprotein, may also cause resistance by pumping Quizartinib out of cells. The bone marrow microenvironment can protect leukemia cells from Quizartinib effect. Adverse effects The most commonly reported treatment-related adverse effects were nausea, vomiting and fatigue. The most prevalent high-grade hematologic AEs included febrile neutropenia, anemia and thrombocytopenia. The most prevalent high-grade non-hematologic AEs had pneumonia and sepsis/septic shock. Hemorrhage appeared mostly in low grade. Dangerous hemorrhages happen mainly in the form of gastrointestinal and cranial bleeding. High-grade QT prolongation developed in some patients, which was also increased by the dosage escalation. Conclusion Quizartinib's efficacy in some FLT3-positive AMLs is limited due to resistance, but a predictive biomarker for this resistance has not yet been identified. Furthermore, a protocol for the appropriate use of Quizartinib in different types of chemotherapy remains undefined. [ABSTRACT FROM AUTHOR]

Leukemia is a group of blood cancers that are classified in four major classes. Within these four classes, many different subtypes exists with similar origin, genetic mutations, and level of maturity, which can make them difficult to distinguish. Despite their similarities, they might respond differently to treatment, and therefore distinguishing between them is of crucial importance. A deranged metabolic phenotype (Warburg effect) is often seen in cancer cells, leukemia cells included, and is increasingly a target for improved diagnosis and treatment. In this study, hyperpolarized 13C NMR spectroscopy was used to characterize the metabolic signatures of the six leukemia cell lines ML‐1, CCRF‐CEM, THP‐1, MOLT‐4, HL‐60, and K562. This was done using [1‐13C]pyruvate and [1‐13C]alanine as bioprobes for downstream metabolite quantification and kinetic analysis on cultured cells with and without 2‐deoxy‐D‐glucose treatment. The metabolic signatures of similar leukemia subtypes could be readily distinguished. This includes ML‐1 and THP‐1, which are of the similar M4 and M5 AML subtypes, CCRF‐CEM and MOLT‐4, which are of the similar T‐ALL lineage at different maturation states, and HL‐60 and K562, which are of the closely related M1 and M2 AML subtypes. The data presented here demonstrate the potential of hyperpolarized 13C NMR spectroscopy as a method to differentiate between leukemia subtypes of similar origin. Combining this method with bioreactor setups could potentially allow for better leukemia disease management as metabolic signatures could be acquired from a single biopsy through repeated experimentation and intervention. [ABSTRACT FROM AUTHOR]

Background and Objectives: The long-term prognosis of acute myeloid leukemia (AML) is challenging due to limited understanding of the molecular markers involved in its development. This study investigates the role of DNA polymerases in AML to offer new insights for diagnosis and treatment. Materials and Methods: A retrospective study on pediatric AML patients with POL gene family mutations from 2021 to 2024 was conducted. Patients were categorized based on risk stratification criteria, and the DAH regimen was used for induction chemotherapy. Bioinformatics analysis integrated data from various databases to identify key genes and develop survival analysis plots and AUC curves. Results: The study included 59 pediatric AML patients, revealing no significant differences in demographic or clinical characteristics between those with and without POL family gene mutations. However, patients with POL gene mutations showed higher complete remission rates after initial DAH chemotherapy (91.67% vs. 59.57%, p = 0.03607), indicating a potential treatment benefit. High expression of four POL genes (POLD1, POLE, POLG, and POLQ) in bone marrow and immune cells suggests their crucial role in hematopoiesis and immune response. Survival analysis across different datasets indicated that AML patients with overexpressed POL family genes had significantly worse outcomes, proposing these genes as potential prognostic biomarkers for AML. Conclusions: This study on pediatric AML demonstrates that POL gene family mutations are associated with higher remission rates post-chemotherapy, indicating their potential as prognostic markers. Bioinformatics analysis emphasizes the significance of these mutations in AML, highlighting their impact on disease prognosis. [ABSTRACT FROM AUTHOR]

Infection is among the most common causes of death in patients with acute myeloid leukemia (AML) after chemotherapy. The anti-tumor effect of the intestinal microbiota in patients with AML is increasingly being recognized. Tigecycline, a broad-spectrum antibiotics, plays a vital role in the anti-infection treatment of AML patients with neutropenia and accompanying infections. Previously, this group reported that long-term use of tigecycline caused coagulation dysfunction in patients with hematological malignancies, increasing the risk of casualties. RNA sequencing was performed on CHO cells before and after tigecycline treatment. Further, the combined analysis of AML prognostic differentially expressed genes revealed 13 genes affected by tigecycline and closely related to AML prognosis. These genes were used for modeling analysis, and the results showed that the prepared model significantly improved the prognostic prediction efficiency for AML patients. The model also explored the correlation between prognosis score and immune cells infiltrating tumors and immune therapy targets. Moreover, 16S sequencing was performed on fecal samples from AML patients before and after tigecycline treatment. The results revealed that tigecycline significantly altered the distribution of intestinal microbiota in AML patients - These changes in microbiota are related to chemotherapy resistance. This study emphasizes the importance of intestinal microbiota in AML prognosis. Thus, the findings of this study show that the long-term use of antibiotics can not only cause dysbiosis of the intestinal microbiota but also indirectly affect the sensitivity of chemotherapy drugs, affecting the prognosis of AML patients. [ABSTRACT FROM AUTHOR]