Abstract 14: Molecular drivers of lineage bias in TP53-mutant therapy-related acute leukemias

Clonal hematopoiesis (CH) is a precursor for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Therapy-related (tr-) leukemias are long-term complications of genotoxic therapies for cancer or autoimmune disease. They often present with a myeloid phenotype, but a subset of patients (pts) may develop tr-ALL. Molecular mechanisms driving the lineage bias of tr-leukemogenesis originating from CH are unknown.We studied 345 tr-MN and 217 tr-ALL pts from six centers in North America. Multiple myeloma (MM) was the most common antecedent malignancy in tr-ALL (25% of pts), and only 4% of tr-MN pts had MM (p< 0.01). 33% of tr-MN pts had complex karyotype, 24% of tr-ALL pts had low hypodiploidy. Other most frequent genetic abnormalities had similar frequencies between tr-MN vs tr-ALL, including mutations in TP53 (30% vs 33%), DNMT3A (16% vs 11%), and KMT2A-rearrangements (8% vs 15%). Given the overlap for common genetic drivers in tr-MN vs tr-ALL, we focused on the most frequent subtype of TP53-mutant (TP53-m) tr-leukemias. We hypothesized that TP53-m CH progresses to tr-AML vs tr-ALL via divergent molecular pathways.To elucidate the molecular differences between tr-TP53-m leukemias, we performed scRNA-seq of bone marrows from healthy individuals (n=4), TP53-m CH (n= 3), TP53-m tr-AML (n= 7) and TP53-m tr-ALL (n= 6). A total of 120,726 cells were analyzed. We compared gene signatures and transcription factor (TF) activities of hematopoietic stem cells (HSCs) vs leukemic blasts. In GSEA, TP53-m HSCs from CH were enriched in fat metabolism pathways (i.e., fatty acid, arachidonic acid, peroxisomal lipid metabolism) when compared to TP53-wild type HSCs from healthy individuals. These metabolic pathways were further enriched in TP53-m AML blasts when compared to CH and healthy stem cells, suggesting a switch in energy metabolism associated with myeloid lineage commitment. AML blasts also had high NLRP3-inflammasome and tumor necrosis factor (TNF) signaling. AML blasts showed higher TF activity of GATA2, CEBPA, LMO2 and KAT6A, which may indicate a block in myeloid differentiation and altered chromatin remodeling. ALL blasts showed increased activity of transcription factors involved in NF-κB signaling, including NFKB, RELA, JUN and AP1 that may promote cell survival and resistance to apoptosis.In interactome analysis, TP53-m AML blasts were characterized by their integrin cell surface interactions, including ITGA5 interaction with CD40LG on T cells, and ITGAV interaction with TGF-β secreted from CD8+ T, NK, and Treg cells. In TP53-m ALL, upregulated TNFα response resulted in increased HLA antigen expression.Collectively, tr-AML and tr-ALL have overlapping genetic characteristics, dominated by TP53-m and aneuploidy. Our data identified key molecular pathways associated with myeloid vs lymphoid bias of leukemogenesis. Citation Format: Diren Arda Karaoglu, Ibrahim Aldoss, Ann-Kathrin Eisfeld, Madina Sukhanova, Yasmin Abaza, Peng Wang, Melissa Tjota, Jeremy Segal, Angela Lager, Carrie Fitzpatrick, Jason Xiaojun Cheng, Sandeep Gurbuxani, Girish Venkataraman, Anand Ashwin Patel, Adam S. Duvall, Michael W Drazer, Todd C Knepper, Daniel A. Arber, Toyosi Odenike, Richard A. Larson, Guido Marcucci, Bijal D Shah, Wendy Stock, Caner Saygin. Molecular drivers of lineage bias in TP53-mutant therapy-related acute leukemias [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 14.