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.

Role of Heterogeneous Nuclear Ribonucleoproteins in the Cancer-Immune Landscape

“…HnRNPK also regulates myeloid cell differentiation and expansion. This effect is due to HnRNPK-mediated AS regulation of RUNX1 , a transcription factor important for myeloid cell differentiation and proliferation [ 9 ]. HnRNPE2 suppressed myeloid differentiation by functioning as a splicing silencer in the MM6 myeloid cell line.…”

“…The hnRNP comprise a highly evolutionary conserved family of RNA-binding proteins (RBP) involved in basic cellular mechanisms, including post-transcriptional regulation (e.g., splicing), mRNA stability, and protein translation, all of which are critical contributors to proteome complexity [ 8 ]. Cancer cells exhibit a higher expression of hnRNP than non-cancer cells [ 9 , 10 , 11 , 12 ]. HnRNP function as tumor drivers by promoting cancer cell proliferation, invasion, inflammation, resistance to cell death, deregulation of metabolic homeostasis, and therapeutic resistance [ 13 ].…”