PhD Candidate Albert Einstein Col. of Med. Bronx, New York, United States
Disclosure(s):
Leah Kravets, MS: No financial relationships to disclose
Introduction/Rationale: Myeloid neoplasms (MN) are characterized by myeloid blast expansion that blocks hematopoietic differentiation and causes cytopenia, a major cause of morbidity and mortality. KRASG12D mutations occur in up to 15% of MN, are enriched in therapy-resistant disease, and are linked to poor prognosis. Currently, no precision medicine strategies exist for KRASG12D-mutant MN. Progress has been limited by the lack of representative models and difficulty distinguishing KRAS-mutant from wildtype cells in patient samples.
Methods: To address this, we used Genotyping of Transcriptomes (GoT), which co-captures single cell RNA-seq and mutational status within the same thousands of individual cells to elucidate specific KRASG12D-driven pathways in preleukemic Clonal Hematopoiesis (CH) and 3 Acute Myeloid Leukemia (AML) patient samples. We also developed a novel transplantable AdenoCreLox KRASG12D mouse model.
Results: In AML, mutant cells formed a distinct inflammatory, stem/progenitor-like population with elevated CD83 expression and quiescent features. In vitro, KRASG12D CD83+ cells displayed higher stemness and reduced differentiation compared to CD83− cells.
An isolated KRASG12D CH sample revealed mutant cell overrepresentation in the myeloid lineages, specifically monocytes and erythrocytes. Treatment with a KRASG12D-specific inhibitor (MRTX1133) restored wildtype erythroid differentiation and downregulated inflammatory genes, including CD83.
Lastly, a KRASG12D mouse model mimicking human disease with extramedullary granulocytic tumors was developed, where CD83 marked mutant cells. Resolution of these phenotypes was achieved with MRTX1133 treatment.
Conclusion: Therefore, KRASG12D drives erythroid differentiation block, monocytic bias, and inflammation, which MRTX1133 reverses. We identify a novel quiescent CD83+ KRASG12D progenitor population in AML and demonstrate the therapeutic potential of MRTX1133 in vivo. Additionally, targeting CD83⁺ quiescent cells may prevent AML progression in KRASG12D patients.
