Subtype Of Acute Myeloid Leukemia Research Articles

A novel risk score model of lactate metabolism for predicting outcomes and immune signatures in acute myeloid leukemia

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

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.

A case of isolated cutaneous myeloid sarcoma preceding acute myeloid leukemia and literature review

Isolated Cutaneous Myeloid Sarcoma (icMS) and Aleukemic Leukemia Cutis (ALC) are cutaneous extramedullary manifestations of leukemia in which leukemic cells infiltrate the skin before they can be identified either in the peripheral blood or in the bone marrow. We report the case of a 67-year-old patient who presented with a rapidly developing cutaneous tumour and scaly, erythematous-squamous plaques. Isolated Cutaneous Myeloid Sarcoma was diagnosed which rapidly progressed to terminal-stage Acute Myeloid Leukemia (AML). To highlight the disease characteristics of the adult-onset icMS and ALC cases that preceded AML we additionally compiled the pertinent literature of case reports of these rare conditions. We identified n=15 previously published icMS/ALC cases with adequately detailed clinical data descriptions. We could confirm the medical experience that icMS/ALC patients have an overall worse prognosis. Moreover, we could identify FAB M5 AML subtype as a significant adverse prognosticator of these patients.

Immunotherapeutic Potential of Mutated NPM1 for the Treatment of Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a malignant disease of the blood and bone marrow that is characterized by uncontrolled clonal proliferation of abnormal myeloid progenitor cells. Nucleophosmin 1 (NPM1) gene mutations are the most common genetic abnormality in AML, detectable in blast cells from about one-third of adults with AML. AML NPM1mut is recognized as a separate entity in the World Health Organization classification of AML. Clinical and survival data suggest that patients with this form of AML often have a more favorable prognosis, which may be due to the immunogenicity created by the mutations in the NPM1 protein. Consequently, AML with NPM1mut can be considered an immunogenic subtype of AML. However, the underlying mechanisms of this immunogenicity and associated favorable survival outcomes need to be further investigated. Immune checkpoint molecules, such as the programmed cell death-1 (PD-1) protein and its ligand, PD-L1, play important roles in leukemogenesis through their maintenance of an immunosuppressive tumor microenvironment. Preclinical trials have shown that the use of PD-1/PD-L1 checkpoint inhibitors in solid tumors and lymphoma work best in novel therapy combinations. Patients with AML NPM1mut may be better suited to immunogenic strategies that are based on the inhibition of the PD-1 immune checkpoint pathway than patients without this mutation, suggesting the genetic landscape of patients may also inform best practice for the use of PD-1 inhibitors.

A case of visual impairment due to HHV-6 encephalitis after allogeneic hematopoietic stem cell transplantation in childhood acute myeloid leukemia-M2 subtype.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a crucial treatment option for children with M2 subtype acute myeloid leukemia (AML). Human herpesvirus 6 (HHV-6) encephalitis following transplantation is a rare postoperative complication, with a poor prognosis and a high fatality rate in allo-HSCT recipients. In this report, a juvenile patient with AMLwas successfully treated after developing visual impairment as a result of HHV-6B encephalitis during allo-HSCT therapy. HHV-6 encephalitis-associated visual impairment after transplantation is rare, and clinical diagnosis and treatment are challenging, requiring more attention in the future.

Effects of imidazole derivatives on cellular proliferation and apoptosis in myeloid leukemia.

Acute promyelocytic leukemia (APL) is the sub-type of Acute myeloid leukemia (AML) which is described by differentiation block at promyelocytic stage and t(15; 17) translocation with All trans retinoic acid (ATRA) and arsenic trioxide (ATO) as standard treatments. Chronic myeloid leukemia (CML) translocation t (19; 22) causes a rise in granulocytes and their immature precursors in the blood. Different mutations cause resistance to first-line tyrosine kinase therapies in CML. Beside drug resistance, leukemia stem cells (LSC) are critical resources for relapse and resistance in APL and CML. The drug toxicity and resistant profile associated with LSC and current therapeutics of APL and CML necessitate the development of new therapies. Imidazoles are heterocyclic nitrogen compounds with diverse cellular actions. The purpose of this research was to assess the anti-leukemic properties of four novel imidazole derivatives including L-4, L-7, R-35, and R-NIM04. Pharmacological and biochemical approaches were used which showed that all four imidazole derivatives interfere with the NB4 cells proliferation, an APL cell line, while only L-7 exhibit anti-proliferative activity against K562 cells, a CML cell line. The anti-proliferative effect of imidazole derivatives was linked to apoptosis induction. Further real-time polymerase chain reaction (RT-PCR) analysis revealed downregulation of AXL-Receptor Tyrosine Kinase (AXL-RTK) and target genes of Wnt/beta-catenin pathway like c-Myc, Axin2 and EYA3. An additive effect was observed after combinatorial treatment of L-7 with standard drugs ATRA or Imatinib on the proliferation of NB4 and K562 cells respectively which was related to further downregulation of target genes of Wnt/beta catenin pathway. Imidazole derivatives significantly reduce proliferation of NB4 and K562 cells by inducing apoptosis, down regulating of AXL-RTK and Wnt/β-catenin target genes.

Acute Myeloid Leukemia among Patients attending Sana’a Hospitals, Yemen: Prevalence, Subtypes and Hematological Patterns

Objectives: Acute myeloid leukemia (AML) is malignant disorder of cells of myeloid lineage in the bone marrow due to chromosomal abnormalities, leading to accumulation of myeloblasts in the bone marrow and infiltration to peripheral tissues. The aim of this study was to determine the prevalence, subtypes and hematological patterns of AML among patients attending Sana’a hospitals, Yemen. Materials and methods: This cross-sectional study was carried out on total 257 patients with hematological malignancies (HMs) during the period from November 1, 2023 to March 31, 2024. Among HMs, there were 79 patients diagnosed with AML by complete blood count (CBC), by Giemsa stained blood/BM films, and by immunophenotyping using flow cytometry. Data was analyzed using SPSS-26. Results: Among 257 patients with HMs, AML was found in 79 patients with prevalence of 30.7%. AML patients included 53 (67.1%) males and 26 (32.9%) females., with M:F ratio of 2:1 and aged between 4 and 80 years, FAB-M2 was the most common subtype of AML in 30 (37.97%) of patients; among them, there were 19 (24.05%) males and 11 (13.92%) females, the M:F ratio is 1.7:1. FAB-M2 was followed by M1 (26.58), M5 (17.2), M3 (7.59), M4 (5.06), M0 (3.8) and M7 (1.26). The hematological patterns included decreased Hb, increased WBC and decreased platelets in 97.5%, 82.3% and 96.2% of patients, respectively. Conclusion: Leukemia was the most prevalent type among hematological malignancies. The prevalence of AML was high and represent the second leukemia type. AML-M2 was the common subtype of AML.

Phosphoproteomics predict response to midostaurin plus chemotherapy in independent cohorts of FLT3-mutated acute myeloid leukaemia

Acute myeloid leukaemia (AML) is a bone marrow malignancy with poor prognosis. One of several treatments for AML is midostaurin combined with intensive chemotherapy (MIC), currently approved for FLT3 mutation-positive (FLT3-MP) AML. However, many patients carrying FLT3 mutations are refractory or experience an early relapse following MIC treatment, and might benefit more from receiving a different treatment. Development of a stratification method that outperforms FLT3 mutational status in predicting MIC response would thus benefit a large number of patients. We employed mass spectrometry phosphoproteomics to analyse 71 diagnosis samples of 47 patients with FLT3-MP AML who subsequently received MIC. We then used machine learning to identify biomarkers of response to MIC, and validated the resulting predictive model in two independent validation cohorts (n=20). We identified three distinct phosphoproteomic AML subtypes amongst long-term survivors. The subtypes showed similar duration of MIC response, but different modulation of AML-implicated pathways, and exhibited distinct, highly-predictive biomarkers of MIC response. Using these biomarkers, we built a phosphoproteomics-based predictive model of MIC response, which we called MPhos. When applied to two retrospective real-world patient test cohorts (n=20), MPhos predicted MIC response with 83% sensitivity and 100% specificity (log-rank p<7∗10-5, HR=0.005 [95% CI: 0-0.31]). In validation, MPhos outperformed the currently-used FLT3-based stratification method. Our findings have the potential to transform clinical decision-making, and highlight the important role that phosphoproteomics is destined to play in precision oncology. This work was funded by Innovate UK grants (application numbers: 22217 and 10054602) and by Kinomica Ltd.

NUP98 oncofusions in myeloid malignancies: An update on molecular mechanisms and therapeutic opportunities.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a heterogeneous molecular landscape. In the pediatric context, the NUP98 gene is a frequent target of chromosomal rearrangements that are linked to poor prognosis and unfavorable treatment outcomes in different AML subtypes. The translocations fuse NUP98 to a diverse array of partner genes, resulting in fusion proteins with novel functions. NUP98 fusion oncoproteins induce aberrant biomolecular condensation, abnormal gene expression programs, and re-wired protein interactions which ultimately cause alterations in the cell cycle and changes in cellular structures, all of which contribute to leukemia development. The extent of these effects is steered by the functional domains of the fusion partners and the influence of concomitant somatic mutations. In this review, we discuss the complex characteristics of NUP98 fusion proteins and potential novel therapeutic approaches for NUP98 fusion-driven AML.

Epigenetic regulation of noncanonical menin targets modulates menin inhibitor response in acute myeloid leukemia

AbstractMenin inhibitors that disrupt the menin-MLL interaction hold promise for treating specific acute myeloid leukemia (AML) subtypes, including those with KMT2A rearrangements (KMT2A-r), yet resistance remains a challenge. Here, through systematic chromatin-focused CRISPR screens, along with genetic, epigenetic, and pharmacologic studies in a variety of human and mouse KMT2A-r AML models, we uncovered a potential resistance mechanism independent of canonical menin-MLL targets. We show that a group of noncanonical menin targets, which are bivalently cooccupied by active menin and repressive H2AK119ub marks, are typically downregulated after menin inhibition. Loss of polycomb repressive complex 1.1 (PRC1.1) subunits, such as polycomb group ring finger 1 (PCGF1) or BCL6 corepressor (BCOR), leads to menin inhibitor resistance by epigenetic reactivation of these noncanonical targets, including MYC. Genetic and pharmacological inhibition of MYC can resensitize PRC1.1-deficient leukemia cells to menin inhibition. Moreover, we demonstrate that leukemia cells with the loss of PRC1.1 subunits exhibit reduced monocytic gene signatures and are susceptible to BCL2 inhibition, and that combinational treatment with venetoclax overcomes the resistance to menin inhibition in PRC1.1-deficient leukemia cells. These findings highlight the important roles of PRC1.1 and its regulated noncanonical menin targets in modulating the menin inhibitor response and provide potential strategies to treat leukemia with compromised PRC1.1 function.

The Role of Epithelial-to-Mesenchymal Transition Transcription Factors (EMT-TFs) in Acute Myeloid Leukemia Progression.

Acute myeloid leukemia (AML) is a diverse malignancy originating from myeloid progenitor cells, with significant genetic and clinical variability. Modern classification systems like those from the World Health Organization (WHO) and European LeukemiaNet use immunophenotyping, molecular genetics, and clinical features to categorize AML subtypes. This classification highlights crucial genetic markers such as FLT3, NPM1 mutations, and MLL-AF9 fusion, which are essential for prognosis and directing targeted therapies. The MLL-AF9 fusion protein is often linked with therapy-resistant AML, highlighting the risk of relapse due to standard chemotherapeutic regimes. In this sense, factors like the ZEB, SNAI, and TWIST gene families, known for their roles in epithelial-mesenchymal transition (EMT) and cancer metastasis, also regulate hematopoiesis and may serve as effective therapeutic targets in AML. These genes contribute to cell proliferation, differentiation, and extramedullary hematopoiesis, suggesting new possibilities for treatment. Advancing our understanding of the molecular mechanisms that promote AML, especially how the bone marrow microenvironment affects invasion and drug resistance, is crucial. This comprehensive insight into the molecular and environmental interactions in AML emphasizes the need for ongoing research and more effective treatments.

Mutant NPM1 marginally impacts ribosome footprint in acute myeloid leukemia cells.

NPM1-mutated acute myeloid leukemia (AML) is the most frequent AML subtype. As wild-type NPM1 is known to orchestrate ribosome biogenesis, it has been hypothesized that altered translation may contribute to leukemogenesis and leukemia maintenance in NPM1-mutated AML. However, this hypothesis has never been investigated. We reasoned that if mutant NPM1 (NPM1c) directly impacts translation in leukemic cells, loss of NPM1c would result in acute changes in the ribosome footprint. Here, we performed ribosome footprint profiling (Ribo-seq) and bulk messenger RNA (mRNA) sequencing in two NPM1-mutated cell lines engineered to express endogenous NPM1c fused to the FKBP (F36V) degron tag (degron cells). Incubation of degron cells with the small compound dTAG-13 enables highly specific degradation of NPM1c within 4hours. As expected, RNA-sequencing data showed early loss of homeobox gene expression following NPM1c degradation, confirming the reliability of our model. In contrast, Ribo-seq data showed negligible changes in the ribosome footprint in both cell lines, implying that the presence of NPM1c does not influence ribosome abundance and positioning on mRNA. While it is predictable that NPM1c exerts its leukemogenic activity at multiple levels, ribosome footprint does not seem influenced by the presence of mutant NPM1.

Halogenated retinoid derivatives as dual RARα and RXRα modulators for treating acute promyelocytic leukemia cells

Acute promyelocytic leukemia (APL), a distinctive subtype of acute myeloid leukemia (AML), is characterized by the t(15; 17) translocation forming the PML-RARα fusion protein. Recent studies have revealed a crucial role of retinoid X receptor α (RXRα) in PML-RARα′s tumorigenesis. This necessitates the development of dual RARα and RXRα targeting compounds for treating APL. Here, we developed a pair of brominated retinoid isomers, 5a and 5b, exhibiting RARα agonistic selectivity among the RAR subtypes and RXRα partial agonistic activities. In the treatment of APL cells, low doses (RARα activation range) of 5a and 5b degrade PML-RARα and strongly induce differentiation, while higher doses (RXRα activation range) induce G2/M arrest and apoptosis in both all-trans retinoic acid (ATRA)-sensitive and resistant cells. We replaced the bromine in 5a with chlorine or iodine to obtain compounds 7 or 8a. Interestingly, the chlorinated compound 7 tends to activate RXRα and induce G2/M arrest and apoptosis, while the iodinated compound 8a tends to activate RARα and induce differentiation. Together, our work underscores several advantages and characteristics of halogens in the rational design of RARα and RXRα ligands, offering three promising drug candidates for treating both ATRA-sensitive and resistant APL.

Patients with TP53-Mutated Acute Myeloid Leukemia Receiving Intensive Induction Therapy Have Superior Outcomes Due to a Higher Rate of Salvage Therapy: A Single Institution, Retrospective Study.

TP53 mutations (TP53m) define the most treatment-refractory acute myeloid leukemia (AML) subtype. Optimal treatment approaches have not been established in this setting. We reviewed our institutional experience to identify therapy sequencing, treatment response, and survival patterns in these patients. This study was a single-center, retrospective cohort analysis. Our cohort includes 86 TP53m and 337 TP53 wild-type (TP53wt) adult AML patients. TP53m AML patients presented with lower bone marrow and peripheral blasts; none presented with hyperleukocytosis. Patients who received intensive treatment up front demonstrated superior overall survival (OS) over those receiving first-line non-intensive therapy (2-year OS 22% versus 7%; p = 0.02). However, the complete remission (CR) rates among the first-line intensive and non-intensive therapy groups were comparable (21.9% and 29.4%, respectively, p = 0.49). The improved OS is therefore attributed to superior cumulative CR in the intensive group. First-line intensively treated patients were more likely to receive and respond to salvage, leading to a cumulative CR rate of 65.7% (versus 29.4%, p = 0.003). Achieving CR at any point is strongly associated with superior survival outcomes with 2-year OS of 31% versus 0% for those not achieving CR ever (p < 0.01). We find that TP53m AML rarely presents with oncological emergencies, suggesting that clinical trial enrollment is feasible in this group. Additionally, in our cohort, intensive induction therapies lead to superior survival outcomes attributed to successful salvage therapy. These data suggest that strategic therapy sequencing and salvage therapy may be important in optimizing outcomes for TP53m AML patients.

Targeting the redox vulnerability of acute myeloid leukaemia cells with a combination of auranofin and vitamin C.

Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by complex molecular and cytogenetic abnormalities. Pro-oxidant cellular redox status is a common hallmark of AML cells, providing a rationale for redox-based anticancer strategy. We previously discovered that auranofin (AUF), initially used for the treatment of rheumatoid arthritis and repositioned for its anticancer activity, can synergize with a pharmacological concentration of vitamin C (VC) against breast cancer cell line models. In this study, we observed that this drug combination synergistically and efficiently killed cells of leukaemic cell lines established from different myeloid subtypes. In addition to an induced elevation of reactive oxygen species and ATP depletion, a rapid dephosphorylation of 4E-BP1 and p70S6K, together with a strong inhibition of protein synthesis were early events in response to AUF/VC treatment, suggesting their implication in AUF/VC-induced cytotoxicity. Importantly, a study on 22 primary AML specimens from various AML subtypes showed that AUF/VC combinations at pharmacologically achievable concentrations were effective to eradicate primary leukaemic CD34+ cells from the majority of these samples, while being less toxic to normal cord blood CD34+ cells. Our findings indicate that targeting the redox vulnerability of AML with AUF/VC combinations could present a potential anti-AML therapeutic approach.

Marine derived macrolide bryostatin 4 inhibits the TGF-β signaling pathway against acute erythroleukemia.

Acute erythroleukemia (AEL) is a rare and highly aggressive subtype of acute myeloid leukemia (AML) with an extremely poor prognosis when treated with available drugs. Therefore, new investigational agents capable of inducing remission are urgently required. Bioinformatics analysis, western blot and qRT-PCR were used to reveal the potential biological mechanism of bryostatin 4 (B4), an antineoplastic macrolide derived from the marine bryozoan Bugula neritina. Then, in vivo experiments were conducted to evaluate the role of transforming growth factor (TGF)-β signaling in the progression of AEL. Our results revealed that the proliferation of K562 cells and TF-1 cells was significantly inhibited by B4 at IC50 values of 37 nM and 52 nM, respectively. B4 inhibited TGF-β signaling and its downstream pathway targets, particularly the phosphorylation of Smad2, Smad3, Ras, C-RAF, ERK1/2, and MEK. B4 also played an important role in cell invasion and migration in K562 cells and TF-1 cells by reducing the protein levels of the mesenchymal cell marker vimentin. Moreover, Flow cytometry and western blot analyses demonstrated that B4 induced apoptosis and initiated G0/G1 phase arrest by modulating mitochondrial dysfunction and cyclin-dependent kinase (CDK) expression. These findings indicated that B4 could inhibit the proliferation, migration, invasion, and TGF-β signaling pathways of AEL cells, thus suggesting that B4 possesses therapeutic potential as a treatment for AEL.

Acute promyelocytic leukemia: the first reported case diagnosed by immunophenotyping in Mozambique

Patients with acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML), often present with severe leucocytosis and thrombocytopenia, which may lead to symptoms that require prompt diagnosis and treatment. Immunophenotyping combined with cytomorphology is a valuable tool for identifying APL patients. We describe the case of a 9-year-old male patient who was diagnosed with APL in July 2022 using immunophenotyping combined with cytomorphology. The patient was treated with chemotherapy and is now in full remission in the maintenance phase. This case demonstrated the importance of timely differential diagnosis using the correct tools, allowing inclusion in the appropriate treatment protocol.

Integrin-α9 overexpression underlies the niche-independent maintenance of leukemia stem cells in acute myeloid leukemia

Leukemia stem cells (LSCs) are widely believed to reside in well-characterized bone marrow (BM) niches; however, the capacity of the BM niches to accommodate LSCs is insufficient, and a significant proportion of LSCs are instead maintained in regions outside the BM. The molecular basis for this niche-independent behavior of LSCs remains elusive. Here, we show that integrin-α9 overexpression (ITGA9 OE) plays a pivotal role in the extramedullary maintenance of LSCs by molecularly mimicking the niche-interacting status, through the binding with its soluble ligand, osteopontin (OPN). Retroviral insertional mutagenesis conducted on leukemia-prone Runx-deficient mice identified Itga9 OE as a novel leukemogenic event. Itga9 OE activates Akt and p38MAPK signaling pathways. The elevated Myc expression subsequently enhances ribosomal biogenesis to overcome the cell integrity defect caused by the preexisting Runx alteration. The Itga9-Myc axis, originally discovered in mice, was further confirmed in multiple human acute myeloid leukemia (AML) subtypes, other than RUNX leukemias. In addition, ITGA9 was shown to be a functional LSC marker of the best prognostic value among 14 known LSC markers tested. Notably, the binding of ITGA9 with soluble OPN, a known negative regulator against HSC activation, induced LSC dormancy, while the disruption of ITGA9-soluble OPN interaction caused rapid cell propagation. These findings suggest that the ITGA9 OE increases both actively proliferating leukemia cells and dormant LSCs in a well-balanced manner, thereby maintaining LSCs. The ITGA9 OE would serve as a novel therapeutic target in AML.

Epigenetic-based differentiation therapy for Acute Myeloid Leukemia

Despite the development of novel therapies for acute myeloid leukemia, outcomes remain poor for most patients, and therapeutic improvements are an urgent unmet need. Although treatment regimens promoting differentiation have succeeded in the treatment of acute promyelocytic leukemia, their role in other acute myeloid leukemia subtypes needs to be explored. Here we identify and characterize two lysine deacetylase inhibitors, CM-444 and CM-1758, exhibiting the capacity to promote myeloid differentiation in all acute myeloid leukemia subtypes at low non-cytotoxic doses, unlike other commercial histone deacetylase inhibitors. Analyzing the acetylome after CM-444 and CM-1758 treatment reveals modulation of non-histone proteins involved in the enhancer–promoter chromatin regulatory complex, including bromodomain proteins. This acetylation is essential for enhancing the expression of key transcription factors directly involved in the differentiation therapy induced by CM-444/CM-1758 in acute myeloid leukemia. In summary, these compounds may represent effective differentiation-based therapeutic agents across acute myeloid leukemia subtypes with a potential mechanism for the treatment of acute myeloid leukemia.

Proteomic profiling reveals ACSS2 facilitating metabolic support in acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by genomic aberrations in oncogenes, cytogenetic abnormalities, and an aberrant epigenetic landscape. Nearly 50% of AML cases will relapse with current treatment. A major source of therapy resistance is the interaction of mesenchymal stroma with leukemic cells resulting in therapeutic protection. We aimed to determine pro-survival/anti-apoptotic protein networks involved in the stroma protection of leukemic cells. Proteomic profiling of cultured primary AML (n = 14) with Hs5 stroma cell line uncovered an up-regulation of energy-favorable metabolic proteins. Next, we modulated stroma-induced drug resistance with an epigenetic drug library, resulting in reduced apoptosis with histone deacetylase inhibitor (HDACi) treatment versus other epigenetic modifying compounds. Quantitative phosphoproteomic probing of this effect further revealed a metabolic-enriched phosphoproteome including significant up-regulation of acetyl-coenzyme A synthetase (ACSS2, S30) in leukemia-stroma HDACi treated cocultures compared with untreated monocultures. Validating these findings, we show ACSS2 substrate, acetate, promotes leukemic proliferation, ACSS2 knockout in leukemia cells inhibits leukemic proliferation and ACSS2 knockout in the stroma impairs leukemic metabolic fitness. Finally, we identify ACSS1/ACSS2-high expression AML subtype correlating with poor overall survival. Collectively, this study uncovers the leukemia-stroma phosphoproteome emphasizing a role for ACSS2 in mediating AML growth and drug resistance.