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Abstract The combination therapy of hypomethylating agents and venetoclax (HMA+Ven) has emerged as a standard of care for acute myeloid leukemia (AML) patients unfit for intensive chemotherapy. Nonetheless, significant clinical challenges persist including relapse and treatment resistance, to which our understanding remains incomplete. Previous studies have revealed genetic (RAS/RTK pathway mutations and TP53 mutations) and phenotypic (monocytic differentiation) resistance mechanisms. In this context, we hypothesized that integrative assessment of both genetic and phenotypic factors could further unveil the contributors of HMA+Ven resistance. To determine the predictors of treatment response, we first analyzed the baseline characteristics of 208 newly diagnosed, secondary, and relapse/refractory AML patients treated with Decitabine and Venetoclax (Dec+Ven). While complex cytogenetics, KRAS and TP53 mutations were significantly associated with treatment resistance, phenotypic factors such as bone marrow cell compositions or French-American-British (FAB) classifications were not. To identify the factors of resistance at the cellular level, we performed a single-cell targeted DNA-antibody sequencing (DAb-seq) on a subset of 33 patients. In total, 60 multi-timepoint bone marrow samples were analyzed, which included five patients with paired baseline-relapse timepoints. From all five patients, we identified that stem-like cells were largely eradicated and replaced by more differentiated cells such as monocyte-like or erythroid-like cells. At relapse, we identified three patterns of phenotypic shifts: monocytic shift, erythroid shift, and mixed monocytic/erythroid shift. The phenotypic shifts were not always associated with the expansion of new genetic mutations, except for in two cases: one patient had monocytic shift accompanied by the expansion of KRAS mutation, and another patient had erythroid shift accompanied by the expansion of NRAS mutation. To examine the mechanisms behind the phenotypic shifts, we performed a single-cell RNA sequencing on three of the relapsed patients. As a result, we confirmed the upregulation of BCL2L1 in the patient with erythroid shift (N=1), and MCL1 in the patients with monocytic shifts (N=2), but not BCL2 in both. These findings are consistent with known dependency of these cells on non-BCL-2 anti-apoptotic proteins such as MCL-1 and BCL-xL. To summarize, we conclude both genetic and phenotypic factors play a role in Dec+Ven resistance. Most importantly, we report that divergent phenotypic transitions, from stem-like toward more differentiated phenotypes (monocytic or erythroid), were frequently observed in AML relapse following Dec+Ven therapy. Close monitoring of phenotypic alterations during HMA+Ven treatment may facilitate the precise identification of AML patients predisposed to relapse. Citation Format: Yi June Kim, Zongrui Li, Abhishek Maiti, Tomoyuki Tanaka, Hidetaka Uryu, Ken Furudate, Kala Hayes, Naval Daver, Naveen Pemmaraju, Tapan M. Kadia, Farhad Ravandi, Nicholas J. Short, Maro Ohanian, Gautam Borthakur, Nitin Jain, Ghayas C. Issa, Lucia Masarova, Steven M. Kornblau, William G. Wierda, Sanam Loghavi, Sa A. Wang, Guillermo Garcia-Manero, Hagop Kantarjian, Courtney D. DiNardo, Marina Y. Konopleva, Koichi Takahashi. Single-cell proteogenomics analysis of AML samples treated with decitabine and venetoclax reveals divergent treatment escape mechanisms 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 (6Suppl): Abstract nr 3400.
Kim et al. (Fri,) studied this question.