Heterogeneous nuclear ribonucleoprotein K is overexpressed in acute myeloid leukemia and causes myeloproliferative disease in mice via altered Runx1 splicing

Abstract

Acute myeloid leukemia (AML) is driven by numerous molecular events that contribute to disease progression. Herein, we identified hnRNP K overexpression as a recurrent abnormality in AML that is associated with inferior patient outcomes. In murine hematopoietic stem and progenitor cells, hnRNP K overexpression altered self-renewal and differentiation potential. Furthermore, murine transplantation models revealed that hnRNP K overexpression resulted in fatal myeloproliferative phenotypes. Using unbiased approaches, we discovered a direct relationship between hnRNP K and RUNX1--a master transcriptional regulator of hematopoiesis often dysregulated in leukemia. Molecular analyses revealed hnRNP K-dependent alternative splicing of RUNX1, resulting in the generation of a functionally distinct isoform. Taken together, we have established hnRNP K as an oncogene in myeloid leukemia that binds RUNX1 RNA, altering its splicing and subsequent transcriptional activity. These findings shed new light on a mechanism of myeloid leukemogenesis, paving the way for new drug discovery efforts. HighlightsO_LIhnRNP K, an RNA binding protein, is overexpressed in AML and correlates with poor clinical outcomes C_LIO_LIhnRNP K overexpression in murine HSPCs drives fatal myeloproliferative phenotypes in mice C_LIO_LIhnRNP Ks oncogenicity can be attributed, at least in part, to its ability to bind and influence the splicing of the RUNX1 transcript C_LI