hnRNP K Overexpression Drives AML Progression By Altering Pathways Critical for Myeloid Proliferation and Differentiation

Acute myeloid leukemia (AML) is a disease largely defined by recurrent genetic and chromosomal abnormalities. As such, The Cancer Genome Atlas' recent detailed examination of the most common genetic abnormalities that drive AML uncovered relatively few novel alterations. However, within this list of recurrently mutated genes was heterogeneous nuclear ribonucleoprotein K (HNRNPK). While previously unknown to impact AML, we recently identified HNRNPK as a haploinsufficient tumor suppressor at the 9q21.32 locus. In contrast to its tumor suppressive roles, hnRNP K is most customarily overexpressed, rather than underexpressed, in several solid tumors.

In this study, we show through FISH analyses, RNA expression profiling, and reverse phase protein array analyses that the HNRNPK gene is amplified with corresponding mRNA and protein overexpression in a sizeable cohort of patients with AML that do not carry a 9q.21.32 deletion. Together, this indicates that hnRNP K may be an uncharacterized oncogene in this context. Increased hnRNP K correlated with decreased event-free and overall survival, increased WBC, and increased bone marrow and peripheral blood blast percentage. High hnRNP K levels also correlated with elevated expression of histone modifiers (e.g., ASH2L and TRIM24), regulators of ribogenesis (e.g., nucleolin and EBP1), and potent oncogenes, such as c-Myc. Together, these observations indicate that increased hnRNP K expression significantly alters the landscape of myeloid biology and may thus contribute to the etiology of AML.

To directly interrogate this possibility in vivo, we generated a Vav-Cre;Hnrnpk^Tg mouse model. In addition to significant differences in hnRNP K expression compared to Vav-Cre mice, Vav-Cre;Hnrnpk^Tg mice exhibited reduced survival, development of transplantable myeloid malignancies, and enhanced HSPC proliferation and differentiation potential. Reflecting data from our patients, Vav-Cre;Hnrnpk^Tg mice also exhibited elevated expression of critical oncogenic pathways such as c-Myc.

Currently, we are examining pharmacologic methods to abrogate the effects of aberrant hnRNP K expression on various activated pathways. Transplant models using diseased bone marrow from Vav-Cre;Hnrnpk^Tg mice are being utilized to evaluate the efficacy of specific pathway inhibitors (i.e., bromodomain inhibitors or bortezomib) in prolonging survival and decreasing leukemic burden. These studies will provide the rationale for potential clinical trails that employ these agents for patients with hnRNP K-overexpressing AML.