3114 – HMGA2 OVEREXPRESSION CONFERS SENSITIVITY TO G2/M INHIBITORS IN ACUTE MYELOID LEUKEMIA

Abstract

Complex karyotype (CK) acute myeloid leukemia (AML), especially those with TP53 anomalies, are particularly resistant to current therapies and remain one of the most heterogeneous and poorly characterized genetic group. Using global transcriptomic analyses, we identified the oncofetal HMGA2 gene as one of the most upregulated gene in CK AML. HMGA2 is a known stem cell gene and we showed, at single cell level, that HMGA2 is indeed expressed in normal hematopoietic stem cells (HSCs) but also in primitive CD34+ leukemic cells. Abnormal re-expression of HMGA2 has been reported in several tumor types and linked to chemo-resistance, advanced tumor grade and poor prognosis. Using a CRISPR/Cas9 genomic screening approach, we identified vulnerabilities in leukemic cells overexpressing HMGA2. Among them, we found that targeting the G2/M cell cycle phase transition was deleterious to those cells. We confirmed these observations using chemical inhibitors of the G2/M regulators ATR, CHK1 and WEE1 and found that these compounds were preferentially active on HMGA2+ CK AML specimens. Our findings thus suggest that HMGA2 is a key functional determinant in AML associated with stem cell features, G2/M perturbation and related drug sensitivity.