Abstract 6507: Using induced pluripotent stem cells to model tyrosine kinase inhibitor response heterogeneity in chronic myeloid leukemia

Abstract Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by the fusion of BCR in chromosome 22 and ABL1 in chromosome 9. The resulting BCR::ABL1 fusion protein transforms the hematopoietic stem cell into a leukemic stem cell (LSC), driving malignant proliferation. CML is managed using targeted cancer therapy with tyrosine kinase inhibitors (TKIs), notably imatinib, which binds to the ATP-binding pocket of BCR::ABL1, inhibiting its kinase activity. While most patients respond well to TKI treatment, about 40% of patients experience suboptimal responses and primary resistance, warranting an in-depth exploration of the underlying molecular causes. Here, we employ BCR::ABL1-expressing induced pluripotent stem cells (iPSCs) as a platform for modelling treatment response heterogeneity in CML, and development of novel therapeutic approaches that convert poor TKI-responders into optimal responders. Our laboratory has previously shown that specific cellular and molecular features in diagnostic patient bone marrow (BM) predict future TKI sensitivity (Krishnan et al., Blood, 2023). Optimal responders show an enrichment of erythroid progenitor populations, an LSC gene expression signature indicating increased BCR::ABL1 activity, as well as aberrant expression of a canonical erythroid transcriptional program (ETP) that is known to induce an erythroid lineage bias. Consistent with an LSC-intrinsic mechanism for TKI sensitivity, hematopoietic stem and progenitor cells (HSPCs) from optimal responders exhibited a profound erythroid progenitor bias in colony-forming assays, coupled with an exquisite TKI sensitivity when compared to those with primary resistance. HSPCs from poor responders exhibited a myeloid bias in colony-forming assays, with myeloid colonies being more TKI resistant as compared to erythroid counterparts. We hypothesize that higher BCR::ABL1 activity in LSCs from optimal responders results in ETP-driven erythroid lineage skewing in vivo, generating a higher proportion of erythroid progenitors which are intrinsically TKI-sensitive. To test our hypothesis, we reprogrammed diagnostic CML bone marrow samples from 3 optimal responders and 3 poor responders into iPSCs and validate their pluripotency and that any mutations and chromosomal aberrations are conserved. Examination of the transcriptome reveals that key CML-related gene programs are conserved from the primary sample to their iPSC-derived counterparts, e.g., MYC gene programs in poor responder primary and iPSC-derived samples. We conclude that iPSCs will provide a useful platform for testing hypotheses accounting for response heterogeneity in CML, as well as uncovering novel therapeutic approaches. Citation Format: John Joson Ng, Lin Ming Lee, Yi Yang Lim, Kian Leong Lee, Fengcong John Ouyang, Vaidehi Krishnan, Sin Tiong Ong. Using induced pluripotent stem cells to model tyrosine kinase inhibitor response heterogeneity in chronic myeloid leukemia [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 6507.