Treatment Of Acute Myeloid Leukemia Research Articles

Longitudinal ultra-sensitive mutation burden sequencing for precise minimal residual disease assessment in AML.

Relapse is one of the major challenges in clinical treatment of acute myeloid leukemia (AML). Though minimal residual disease (MRD) monitoring plays a crucial role in quantitative assessment of the disease, molecular MRD analysis has been mainly limited to patients diagnosed with gene fusions and NPM1 mutations. Here, we report a longitudinal ultra-sensitive mutation burden (UMB) monitoring strategy for accurate MRD analysis in AML patients regardless of genetic abnormality types. Using a Quantitative Blocker Displacement Amplification (QBDA) sequencing panel with limit of detection below 0.01% variant allele frequency (VAF), a hazard ratio of 14.8 (p < 0.001) is observed in cumulative incidence of relapse analysis of 20 patients with ≥ 2 samples during complete remission (CR). The ROC area under curve (AUC) is 0.98 when predicting relapse within 30 weeks of CR timepoint 2 (N = 20). Furthermore, we demonstrate quantitating VAF below 0.01% is essential for accurate relapse prediction.

Loop33 × 123 CAR-T targeting CD33 and CD123 against immune escape in acute myeloid leukemia.

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. 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. 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. 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.

Succinate dehydrogenase deficiency-driven succinate accumulation induces drug resistance in acute myeloid leukemia via ubiquitin-cullin regulation.

Drug resistance is vital for the poor prognosis of acute myeloid leukemia (AML) patients, but the underlying mechanism remains poorly understood. Given the unique microenvironment of bone marrow, we reasoned that drug resistance of AML might rely on distinct metabolic processes. Here, we identify succinate dehydrogenase (SDH) deficiency and over-cumulative succinate as typical features in AML, with a marked function in causing the resistance of AML cells to various anti-cancer therapies. Mechanistically, succinate promotes the accumulation of oncogenic proteins in a manner that precedes transcriptional activation. This function is mediated by succinate-triggered upregulation of ubiquitin-conjugating enzyme E2M (UBC12) phosphorylation, which impairs its E2 function in cullins neddylation. Notably, decreasing succinate by fludarabine can restore the sensitivity of anti-cancer drugs in SDH-deficient AML. Together, we uncover the function of succinate in driving drug resistance by regulating p-UBC12/cullin activity, and indicate reshaping succinate metabolism as a promising treatment for SDH-deficient AML.

Prioritization of Eleven-Nineteen-Leukemia Inhibitors as Orally Available Drug Candidates for Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is the second most prevalent and fatal form of leukemia. The growth of AML cells harboring oncogenic MLL rearrangements relies on the YEATS domain-containing protein ENL. Many small molecule inhibitors targeting ENL have been developed. To prioritize these inhibitors for in vivo studies, a NanoBRET system was introduced to evaluate their cellular permeability and potency. This screening identified inhibitor 13 as a promising candidate. This inhibitor has remarkable metabolic stability and potent antiproliferative effects on MLL-fusion leukemia cell lines. In AML-xenografted mice, inhibitor 13 significantly improved survival. Subsequent optimization efforts led to the development of SR-C-107 (R), which exhibited strong activity against AML both at the cellular level (CC50(MOLM-13): 1.25 ± 0.18 μM; CC50(MV4-11): 0.81 ± 0.15 μM) and in vivo. These findings establish SR-C-107 (R) as a compelling candidate for AML treatment and lay the groundwork for the development of next-generation AML inhibitors.

Outcomes with intensive treatment for acute myeloid leukemia: an analysis of two decades of data from the HARMONY Alliance.

Since 2017, targeted therapies combined with conventional intensive chemotherapy have started to improve outcome of patients with acute myeloid leukemia (AML). However, even before these innovations outcomes with intensive chemotherapy have improved, which has not yet been extensively studied. Thus, we used a large pan-European multicenter dataset of the HARMONY Alliance to evaluate treatment-time dependent outcomes over two decades. In 5359 AML patients, we compared the impact of intensive induction therapy on outcome over four consecutive 5-year calendar periods from 1997 to 2016. During that time, the 5- year survival of AML patients improved significantly, also across different genetic risk groups. In particular, the 60-day mortality rate has dropped from 13.0% to 4.7% over time. The independent effect of calendar periods on outcome was confirmed in multivariate models. Improvements were documented both for patients.

10-Year Real-World Data on Acute Myeloid Leukemia:

Introduction: Despite advances in Acute Myeloid Leukemia (AML) diagnosis and treatment, the outcomes in low- and middle-income countries (LMIC) are far apart from those in high-income countries (HIC). Objective: To describe the clinical features and outcomes of AML patients in Brazil's public health system, we conducted a retrospective analysis of all cases of non-promyelocytic AML diagnosed within 10 years (2007- 2017) in northeastern Brazil, Bahia. Methodology: We analyzed the real-life outcomes of 62 patients diagnosed with non-promyelocytic AML between 2007 and 2017 at a university hospital in Northeast Brazil. We classified patients using the European LeukemiaNet 2022 guideline into favorable (n=8), intermediate (n=18), and adverse risk (n=7) groups. Twenty-nine were not otherwise classified because no cytogenetic and/or molecular tests were available at diagnosis. Results: Allogeneic bone marrow transplant (alloBMT) was performed in 16 patients (37%). Median overall survival (mOS) was seven months. Among patients receiving alloBMT, mOS was 49 months, while for the chemotherapy group, it was six months (P = 0.003). For 10-year real-life data, we found complete remission of 53%, 5-year OS of 27%, and a mortality rate during induction therapy of 27%, inferior to HIC. Conclusion: Inferior outcomes found in LMIC result from a multifactorial scenario and an unmet need in the worldwide panorama of AML.

The outcome of haematopoietic stem cell transplantation in a patient with STAT1 gain-of-function: a case report

Background: The human signal transducer and activator of transcription 1 (STAT1) is a latent cytoplasmic transcription factor and one of seven members of the STAT family. Autosomal dominant (AD) STAT1 gain-of-function (GOF), characterized by enhanced phosphorylation of the tyrosine-701 residue and STAT1 activation, is commonly associated with chronic mucocutaneous candidiasis (CMCC), immunodeficiency, aneurysms, malignancies, and autoimmune phenomena. The best management strategies for patients with STAT1 GOF remain unclear. Typically, the standard care includes supportive treatments such as antimicrobial prophylaxis, either alone or combined with immunoglobulin replacement therapy. Biological therapies such as JAK inhibitors have been shown to alleviate symptoms of infection and autoimmune disorders in patients with STAT1 GOF mutations. However, there is a lack of long-term outcome data for JAK inhibition. Hematopoietic stem cell transplantation (HSCT) is an alternative treatment option for a subset who experience a persistent disease course despite conventional therapy. However, the effectiveness of HSCT for this condition is not yet well established. Methods: Our patient’s medical records were analyzed retrospectively, including her medical history. Results: We present the outcome of HSCT performed on a 27-year-old female with STAT1 GOF, conducted as a treatment for acute myeloid leukemia (AML). Conclusion: HSCT may serve as an alternative and potentially curative treatment for certain STAT1 GOF patients with progressive, life-threatening conditions that do not respond to conventional therapies. Additional research is needed to improve the management of these patients. Statement of Novelty: We present a novel case study of HSCT as a treatment for AML in a 27-year-old patient with STAT1 GOF, highlighting the potential for curative outcomes in progressive, life-threatening conditions unresponsive to conventional therapies. This case contributes to the limited body of evidence supporting the efficacy and challenges of HSCT in STAT1 GOF patients.

Discovery of CRBN-Dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library.

Small molecules promoting protein-protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While cereblon molecular glue degraders containing glutarimide scaffolds have been approved for treatment of multiple myeloma and acute myeloid leukemia, the design of new therapeutically relevant monovalent degraders remains challenging. We report here an approach to glutarimide-containing molecular glue synthesis using multicomponent reactions as a central modular core-forming step. Screening the resulting library identified HRZ-1 derivatives that target casein kinase 1 α (CK1α) and Wee-like protein kinase (WEE1). Further medicinal chemistry efforts led to identification of selective monovalent WEE1 degraders that provide a potential starting point for the eventual development of a selective chemical degrader probe. The structure of the hit WEE1 degrader complex with CRBN-DDB1 and WEE1 provides a model of the protein-protein interface and ideas to rationalize the observed kinase selectivity. Our findings suggest that modular synthetic routes combined with in-depth structural characterization give access to selective molecular glue degraders and expansion of the CRBN-degradable proteome.

The combination of venetoclax and quercetin exerts a cytotoxic effect on acute myeloid leukemia

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

Homoharringtonine in the treatment of acute myeloid leukemia: A review.

Acute myeloid leukemia (AML) is a hematological malignancy characterized by the accumulation of immature myeloid precursor cells. Over half of AML patients fail to achieve long-term disease-free survival under existing therapy, and the overall prognosis is poor, necessitating the urgent development of novel therapeutic approaches. The plant alkaloid homoharringtonine (HHT), which has anticancer properties, was first identified more than 40 years ago. It works in a novel method of action that prevents the early elongation phase of protein synthesis. HHT has been widely utilized in the treatment of AML, with strong therapeutic effects, few toxic side effects, and the ability to enhance AML patients' prognoses. In AML, HHT can induce cell apoptosis through multiple pathways, exerting synergistic antitumor effects, according to clinical and pharmacological research. About its modes of action, some findings have been made recently. This paper reviews the development of research on the mechanisms of HHT in treating AML to offer insights for further research and clinical therapy.

Identification of single-cell blasts in pediatric acute myeloid leukemia using an autoencoder.

Pediatric acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis and high relapse rate. Current challenges in the identification of immunotherapy targets arise from patient-specific blast immunophenotypes and their change during disease progression. To overcome this, we present a new computational research tool to rapidly identify malignant cells. We generated single-cell flow cytometry profiles of 21 pediatric AML patients with matched samples at diagnosis, remission, and relapse. We coupled a classifier to an autoencoder for anomaly detection and classified malignant blasts with 90% accuracy. Moreover, our method assigns a developmental stage to blasts at the single-cell level, improving current classification approaches based on differentiation of the dominant phenotype. We observed major immunophenotype and developmental stage alterations between diagnosis and relapse. Patients with KMT2A rearrangement had more profound changes in their blast immunophenotypes at relapse compared to patients with other molecular features. Our method provides new insights into the immunophenotypic composition of AML blasts in an unbiased fashion and can help to define immunotherapy targets that might improve personalized AML treatment.

Bone marrow stromal cells enhance differentiation of acute myeloid leukemia induced by pyrimidine synthesis inhibitors.

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

A potent dual inhibitor targeting COX-2 and HDAC of acute myeloid leukemia cells.

Acute myeloid leukemia (AML) is an aggressive cancer with complex issues of drug resistance and a poor prognosis; thus, effective therapeutics is urgently needed for AML. In this study, we designed and synthesized dual cyclooxygenase-2 (COX-2) and histone deacetylase (HDAC) inhibitors, IMC-HA and IMC-OPD, and applied them for the treatment of AML. IMC-HA comprised a COX-2 inhibitor skeleton of indomethacin (IMC) and an HDAC inhibitor moiety of the hydroxamic group and was found to exhibit potent antiproliferative activity against AML cells (THP-1 and U937) and low cytotoxicity toward normal cells. Molecular docking simulations suggested that IMC-HA had a high binding affinity for HDAC and COX-2, with binding energies of -6.8 and -9.0kcal/mol, respectively. Mechanistic studies revealed that IMC-HA induced apoptosis and G0/G1 phase arrest in AML cells, which were characterized by alterations in the expression of apoptotic and cell cycle-related proteins. Further study demonstrated that IMC-HA also inhibited the MEK/ERK signaling pathway in AML cells. Overall, we believe that IMC-HA could serve as a potent COX-2/HDAC dual inhibitor and improve the treatment of AML.

Membrane Antigen Targeting in Acute Myeloid Leukemia Using Antibodies or CAR-T Cells.

This review explores the emerging area of the therapeutic use of antibodies and chimeric antigen receptor (CAR)-T cells for the treatment of acute myeloid leukemia (AML). Through a detailed analysis of the existing literature, this paper highlights the different categories of AML antigens for immunotherapeutic targeting, the most recent applications on antibodies, including bispecific immune cell engagers and CAR-T cells, to the therapy of patients with refractory/relapsing AML The studies performed in AML patients using BisAbs and CAR-T cells have shown that only a limited number of AML patients show sustained responses to these therapies, thus underlying AML heterogeneity as a major challenge. Several studies have addressed the potential mechanisms underlying the resistance of AMLs to antibody-directed immunotherapies. A better understanding of the barriers hampering the successful development of AML immunotherapy is required. However, in spite of the limitations, the studies recently carried out have shown the peculiar sensitivity of some AML subtypes to immunotherapy and have provided the basis for future studies, such as multiplex antigen targeting, which hold the promise of successful development.

Evaluating Fitness in Older Acute Myeloid Leukemia Patients: Balancing Therapy and Treatment Risks.

Assessing the suitability of older adults with acute myeloid leukemia (AML) for intensive chemotherapy or stem cell transplantation remains a long-standing challenge. Geriatric assessment, which involves the evaluation of multiple dimensions of health, may influence a patient's ability to tolerate intensive or mild-intensity approaches, including treatment-related mortality. Prospective studies are required to validate different fitness criteria, in addition to making it possible to compare the effectiveness of geriatric assessment-based fitness against other criteria, in order to identify which aspects of geriatric assessment are linked to treatment tolerance. It is hoped that validation studies will include different groups of patients receiving either intensive or lower-intensity chemotherapy. At a minimum, geriatric assessment should involve the measurement of the comorbidity burden, cognition, physical function, and emotional health-factors previously associated with mortality in AML. These assessments should be conducted before starting chemotherapy in order to minimize the treatment's impact on the results. While treatment tolerance has traditionally been evaluated through toxicity rates in solid tumor patients, AML treatment often results in high toxicity rates regardless of the intensity. Therefore, early mortality should be the primary endpoint for assessing treatment tolerance, given its significant and clear implications. Other important endpoints might include declines in functional status and quality of life and treatment adjustments or discontinuation due to toxicity. Validating these fitness criteria is essential for guiding treatment choices, improving supportive care, determining trial eligibility, interpreting study outcomes, and informing drug labeling.

Identification of ANXA1 as a Novel Upstream Negative Regulator of Notch1 Function in AML.

Abnormal Notch1 expression has an important role in tumorigenesis. However, upstream control mechanisms for Notch1 are still insufficiently understood. Acute myeloid leukemia (AML) is one of the most common and lethal blood malignancies with limited possibilities for treatment. Thus, new therapeutic targets are urgently needed to improve current ineffective therapies. Herein, high Annexin A1 (ANXA1) expression is found correlated with hyperproliferation of AML cells, and then ANXA1 is identified as a novel negative regulator of Notch1 function in AML. Mechanistically, ANXA1 directly bound to the intracellular domain of Notch1 (NICD) to target this tumor suppressor for degradation. Furthermore, NICD executed its tumor suppressive function through activation of the p15 promoter. Thus, ablation of the Notch1-p15-mediated tumor suppression by ANXA1 provided a novel mechanism of AML proliferation. In human AML patients, a mutual exclusive relation is discovered between ANXA1 and Notch1/p15, corroborating mechanistic discovery. On the basis of these results, it is reasonably speculated that targeting ANXA1 would provide an effective approach for treatment of AML. In support of this new therapeutic paradigm, provided proof-of-concept data by antagonizing ANXA1 using NICD inhibitory peptides.

SPAG6 overexpression decreases the pro-apoptotic effect of daunorubicin in acute myeloid leukemia cells through the ROS/JNK MAPK axis in a GSTP1-dependent manner.

As a malignant hematological disease, the incidence of acute myeloid leukemia (AML) has exhibited an upward trend in recent years. Nevertheless, certain limitations persist in the treatment of AML. Sperm-associated antigen 6 (SPAG6) has been implicated in the onset and progression of various human cancers, with its expression levels significantly elevated in AML. Consequently, we undertook a series of experiments to investigate the role and underlying mechanisms of SPAG6 in AML cell lines. In the in vitro experiments of this study, DEPs and GO and KEGG enrichment analysis subsequent to SPAG6 down-regulation were detected by TMT. CCK8 was employed to determine cell viability. The levels of apoptosis and ROS were measured by flow cytometry. In the in vivo experiments, a xenografted tumor model was constructed, and the expression of SPAG6 and GSTP1 in tumor tissues was detected by IHC. Ultimately, our findings indicated that over-expression of SPAG6 promoted cell growth and decreased reactive oxygen species (ROS) and malondialdehyde levels. Furthermore, SPAG6 knockdown was found to diminish mitochondrial membrane potential and facilitate cell apoptosis. In vivo, SPAG6 could also promote tumor growth, suggesting that SPAG6 may serve as a pro-tumor factor. In addition, daunorubicin (DNR) may cause oxidative stress and initiate apoptosis, resulting in oxidative damage to AML cells. However, the overexpression of SPAG6 may attenuate the efficacy of DNR. This was due to SPAG6 promoted GSTP1 expression, thereby reducing ROS levels. Simultaneously, the elevation of GSTP1 and JNK complex may reduce the expression of p-JNK and inhibit the activation of JNK pathway, which might inhibit cell apoptosis. In conclusion, our experiments suggested that upregulated SPAG6 might mitigate the pro-apoptotic effects of DNR through ROS/JNK MAPK axis in a GSTP1-dependent manner.

Discovery of IRAK1/4/pan-FLT3 Kinase Inhibitors as Treatments for Acute Myeloid Leukemia

Discovery of IRAK1/4/pan-FLT3 Kinase Inhibitors as Treatments for Acute Myeloid Leukemia

Up-Regulation of miR-625-5p Correlates with Suppressed Sox2, Increased Apoptosis, and Cell Cycle Arrest via The PI3K/AKT Signalling Pathway in Acute Myeloid Leukaemia

Background: Up-regulation of the microRNA-625 and abnormal expression of the Sox2 gene have been studied and seen in several tumors. Few reports have also shown the aberrant expression of miR-625 and Sox2 expression in various cancers. Several studies have also confirmed that phosphatidylinositol 3' -kinase /protein kinase B pathways regulate hematological malignancies, including Acute Myeloid Leukemia (AML). Thus, this study aimed to investigate the effects of mir-625 up-regulation on proliferation, apoptosis, and cell cycle by targeting the Sox2 gene via the downstream Akt signaling pathway and cell cycle regulators, such as p21, p27, and cyclin E in the KG-1 cell line. Materials and Methods: Cells obtained from the KG-1 cell line were cultured and transfected with plasmid DNA (miR-625) and scrambled as the control using the Lonza electroporation system. Flow cytometry was used to evaluate cell cycle, proliferation, and apoptosis. Relative gene expression was validated by qRT-PCR. All data were analyzed using graph pad prism 7.01 and REST 2009. Results: KG-1 cells transfected with the mir625-GFP construct showed decreased proliferation, increased apoptosis, and induced cell cycle arrest. Low levels of Sox2, p21, cyclin E, and up-regulation of p27 were confirmed and validated by qRT-PCR ( P &lt; 0.05 ). Conclusion: MiR-625 can be a promising approach to aid in the treatment of AML. However, further studies are required in this field

Microbial metabolomics in acute myeloid leukemia: From pathogenesis to treatment.

Acute myeloid leukemia (AML), the most common leukemia in adults, is a biologically heterogeneous disease arising from clonally proliferating hematopoietic stem cells. Increased appreciation of novel genetic methods has improved the understanding of AML biology. Recently, the emerging field of metabolomics has indicated qualitative and quantitative alterations in metabolic profiles in AML pathogenesis, progression and treatment. Multiple metabolic and molecular pathways regulate human metabolism and host-microbiome interactions may significantly affect this biochemical machinery. Microbiota have been found to play a significant role in hematopoietic function, metabolism and immunity, contributing to AML occurrence. A large number of studies have highlighted the importance of the composition and diversity of the gut microbiota (GM) in response to treatment and prognosis in AML. Moreover, strong evidence emphasizes the detrimental link between dysbiosis and infectious complications, a leading cause of morbidity and mortality for patients with AML. Several microbiota-related mechanisms have been linked to particular changes in host physiology so far, and microbial-derived metabolites belong to one of the most important. Circulating in the body, they modulate human conditions both locally and systemically. The extensive and diverse repertoire of bacterial metabolic functions plays a critical role in numerous processes, including leukemogenesis. Integrative analysis of microbiome and metabolome data is a promising avenue for better understanding the complex relationship between the microbiota, biochemical alterations and AML pathogenesis to effectively prevent, treat and mitigate its outcomes. This review concentrates on the pathologic roles and therapeutic implications of microbe-derived metabolites in AML settings.