Molecular Landscape Of Acute Myeloid Leukemia Research Articles

Abstract 6206: Molecular stratification of AML: Integrative genomic and immune profiling points to high risk subgroup and targetable molecular drivers

Abstract Background: Acute Myeloid Leukemia (AML) is a complex hematological malignancy characterized by clinical diversity. The ability to accurately subtype patients can inform prognosis and guide therapeutic approaches. With the integration of multi-omics data, it is possible to elucidate the molecular mechanisms underpinning unique AML subtypes, with intent to identify potential drug targeting pathways in a precision medicine strategy. Method: RNAseq datasets from Beat-AML (discovery, N=462), TCGA-AML (validation, N=173), and Leucegene (validation, N=452) were analyzed through non-negative matrix factorization to delineate distinct transcriptomic-driven molecular subtypes within AML. A curated set of the top 1,000 most variable genes was utilized to minimize analytical noise. GSVA was used for pathway analyses across Hallmark, KEGG, Reactome, and the immune microenvironment was characterized via xCell. Recurring DNA variants were examined in each subtype. Clinical outcomes of each subtype were analyzed using the Kaplan-Meier method and assessed by a log-rank test. These insights were subsequently validated in two independent cohorts - TCGA AML and Leucegene. The most influential components of immunological effector mechanisms, which characterize poor prognostic subpopulation, were assessed using bootstrap forest partitioning as a feature selection technique. Results: Our Beat-AML analysis identified 5 distinct clusters. Cluster 3 consisted of 20% of AML cases (n=86), and displayed a worse overall survival with a HR (95% CI) of 1.41 (1.03, 1.92, P=0.03). This cluster was characterized by three co-mutations: FLT3, NPM1, and DNMT3A. Pathway analysis highlighted biological processes key to antibody therapy intervention, specifically complement pathways, NK cell cytotoxicity, and FCGR-mediated phagocytosis as enriched within this subpopulation. Concurrently, oncogenic (PI3K/AKT/MTOR, TGFB, NOTCH) and metabolic pathways (fatty acid and oxidative phosphorylation) were activated. Immune profiling indicated increased levels of M2 macrophages. Using bootstrap forest partitioning, C2 and ITGAM were identified as key genes defining cluster 3. These observations were confirmed in TCGA AML and Leucegene cohorts. Conclusion: Our comprehensive analysis identified a distinct high-risk AML subgroup characterized by unique genomic, transcriptomic, and immunological patterns. The combined presence of NPM1/FLT3-ITD and DNMT3A mutations in cluster 3—each previously attributed with varied prognostic outcomes—warrants in-depth biological investigation. With these consistent AML subgroup results identified across three independent cohorts (total of 1,087 patients), we highlight the complexities within the molecular landscape of AML and emphasize the need for tailored therapeutic approaches - a transformative shift in AML treatment. Citation Format: Kubra Karagoz, Lauren Brady, Brandon Higgs, Han Si. Molecular stratification of AML: Integrative genomic and immune profiling points to high risk subgroup and targetable molecular drivers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6206.

Pattern of Somatic Mutation Changes from Diagnosis to Relapse Following Allogeneic Hematopoietic Cell Transplantation (alloHCT) for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS)

Pattern of Somatic Mutation Changes from Diagnosis to Relapse Following Allogeneic Hematopoietic Cell Transplantation (alloHCT) for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS)

Targeting Tyrosine Kinases in Acute Myeloid Leukemia: Why, Who and How?

Acute myeloid leukemia (AML) is a myeloid malignancy carrying a heterogeneous molecular panel of mutations participating in the blockade of differentiation and the increased proliferation of myeloid hematopoietic stem and progenitor cells. The historical “3 + 7” treatment (cytarabine and daunorubicin) is currently challenged by new therapeutic strategies, including drugs depending on the molecular landscape of AML. This panel of mutations makes it possible to combine some of these new treatments with conventional chemotherapy. For example, the FLT3 receptor is overexpressed or mutated in 80% or 30% of AML, respectively. Such anomalies have led to the development of targeted therapies using tyrosine kinase inhibitors (TKIs). In this review, we document the history of TKI targeting, FLT3 and several other tyrosine kinases involved in dysregulated signaling pathways.

Relapse of Acute Myeloid Leukemia after Allogeneic Stem Cell Transplantation: Prevention, Detection, and Treatment.

Acute myeloid leukemia (AML) is a phenotypically and prognostically heterogeneous hematopoietic stem cell disease that may be cured in eligible patients with intensive chemotherapy and/or allogeneic stem cell transplantation (allo-SCT). Tremendous advances in sequencing technologies have revealed a large amount of molecular information which has markedly improved our understanding of the underlying pathophysiology and enables a better classification and risk estimation. Furthermore, with the approval of the FMS-like tyrosine kinase 3 (FLT3) inhibitor Midostaurin a first targeted therapy has been introduced into the first-line therapy of younger patients with FLT3-mutated AML and several other small molecules targeting molecular alterations such as isocitrate dehydrogenase (IDH) mutations or the anti-apoptotic b-cell lymphoma 2 (BCL-2) protein are currently under investigation. Despite these advances, many patients will have to undergo allo-SCT during the course of disease and depending on disease and risk status up to half of them will finally relapse after transplant. Here we review the current knowledge about the molecular landscape of AML and how this can be employed to prevent, detect and treat relapse of AML after allo-SCT.

Prognostic stratification in the treatment of AML.

Current treatment of acute myeloid leukemia (AML) still relies on intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). AML is a heterogeneous neoplasm characterized by distinct chromosomal and genetic abnormalities. Recent comprehensive gene analyses have highlighted distinct genetic subgroups that are associated with different responses to chemotherapy. Therefore, the molecular landscape of AML is fundamental to the development of novel therapeutic approaches and provides opportunities for individualization of therapy. In addition, the age-related incidence of clonal hematopoiesis is high, affecting nearly 10% of healthy people more than 65 years of age. Clonal hematopoiesis is confirmed by the presence of mutations related to AML including genes involved in DNA methylation, chromatin modification and RNA splicing. In the analysis of gene mutation profiles in secondary AML (s-AML) from myelodysplastic syndromes and myeloproliferative neoplasms, secondary-type gene mutations were identified with >95% specificity in s-AML as compared with de novo AML, including RNA splicing, chromatin modification and cohesion complex genes, and were highly associated with poor responses to chemotherapy as well as TP53 mutation. It is important to identify genetic subgroups at relatively high-risk of relapses who should receive allogeneic HSCT during the first remission. In this review, prognostic stratification for individualized treatment of AML is discussed.

Diagnosis and Therapy of Acute Myeloid Leukemia in the Era of Molecular Risk Stratification.

The diagnosis and risk stratification of acute myeloid leukemia (AML) primarily rely on morphologic analysis and assessment of karyotype by chromosome banding analysis. For decades, standard AML induction therapy has utilized the combination of anthracyclines and cytarabine. Despite the use of postremission therapy, less than half of patients with AML will be cured of their disease. Allogeneic hematopoietic stem cell transplantation combines cytoreductive chemotherapy with adoptive immunotherapy and may cure patients who fail chemotherapy alone. Recent advances in next-generation sequencing have yielded important insights into the molecular landscape of AML with normal karyotype. Integrated prognostic models incorporating somatic mutation analyses may outperform prediction based on conventional clinical and cytogenetic factors alone. We review the evolution of risk profiling of AML from the cytogenetic to molecular era and describe the implications for AML diagnosis and postremission therapy.