hnRNP K Is a Haploinsufficient Tumor Suppressor that Regulates Proliferation and Differentiation Programs in Hematologic Malignancies

Abstract

Summary hnRNP K regulates cellular programs and changes in its expression and mutational status have been implicated in neoplastic malignancies. To directly examine its role in tumorigenesis, we generated a mouse model harboring an Hnrnpk knock-out allele (Hnrnpk+/−). Hnrnpk haploinsufficiency resulted in reduced survival, increased tumor formation, genomic instability, and the development of transplantable hematopoietic neoplasms with myeloproliferation. Reduced hnRNP K expression attenuated p21 activation, downregulated C/EBP levels, and activated STAT3 signaling. Additionally, analysis of samples from primary acute myeloid leukemia patients harboring a partial deletion of chromosome 9 revealed a significant decrease in HNRNPK expression. Together, these data implicate hnRNP K in the development of hematological disorders and suggest hnRNP K acts as a tumor suppressor.

Aberrant hnRNP K expression: All roads lead to cancer

“…Additionally, qRT-PCR analyses revealed that deletion of the 9q21.32 locus significantly reduced HNRNPK expression in patients with AML. 41 Critically, 8 of 12 patients had deletion of this 9q21.32 region as their sole karyotypic abnormality, suggesting reduced HNRNPK expression directly contributes to the pathogenesis of AML.…”

“…41 Using mouse embryo fibroblasts (MEFs) and haematopoietic stem progenitor cells (HSPCs) in cytokine-dependent colony formation assays, we determined that reduced hnRNP K expression directly resulted in an increase in cellular proliferation. Molecularly, this increased proliferation was directly attributed to hnRNP K's inability to transcriptionally activate p21 when its levels were reduced, supporting the notion that hnRNP K has tumor suppressive functions.…”

“…However, other striking phenotypes observed in haploinsufficient Hnrnpk mice were not related to increased cancer risk, but rather developmental defects. 41 Hnrnpk haploinsufficiency resulted in mice being born at a sub-mendelian ratio, extreme runtedness, a propensity for facial malformations, and a significant neonatal lethal phenotype. Analogous to our observations in mice, pediatric patients with germline HNRNPK mutations (c.953 C 1dup and c.257G > A; respectively) have been recently described.…”

“…43 However, perhaps the most striking evidence that hnRNP K is required for development stems from our observation that biallelic loss of Hnrnpk results in an embryo lethal phenotype prior to day 13.5 (E13.5). 41 Given that hnRNP K has been previously shown to transcriptionally regulate Mdm2 expression, 10,11 we postulated that bi-allelic Hnrnpk loss may potentially result in an embryo-lethal phenotype that is similar to loss of Mdm2 (i.e; an inability to negatively regulate p53-dependent apoptosis in utero). 44 However, when we generated Hnrnpk C/¡ ;Trp53 C/¡ mice and then performed sibling matings, we did not rescue the Hnrnpk-null embryo-lethal phenotype.…”

“…With the development of an Hnrnpk haploinsufficient mouse model, we have made initial strides in examining the tumor suppressive functions of hnRNP K and delineated the importance of reduced hnRNP K expression in cancer development through the p53/p21-and C/EBPpathways. 41 As a result, this model system could become an effective pre-clinical platform to test therapies for patients with AML who harbor a 9q21.32 deletion. In these studies, standard frontline therapies could be used in combination with agents that antagonize the Mdm2-dependent degradation of p53, such as Nutlin-3, DS-3032b, or RG7112 in order to "re-engage" the p53 pathway.…”