hnRNP K Overexpression Synergizes with Mutant NPM1 to Drive Acute Myeloid Leukemia Progression

• Published in: Blood 2014-12, Vol.124 (21), p.2382-2382
• Main Authors: Gallardo, Miguel, Lee, Hun Ju, Zhang, Xiaorui, Pageon, Laura R., Multani, Asha, Reschke, Markus, Clohessy, John G, Quintás-Cardama, Alfonso, Andreeff, Michael, Kornblau, Steven M., Pandolfi, Pier Paolo, Post, Sean M.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V124.21.2382.2382

NPM1 mutations are one of the most common alterations observed in acute myeloid leukemia (AML). When coupled with wild type FLT3 status in cytogenetically normal (CN) patients, NPM1 mutations confer favorable prognoses compared with other alterations. However, a subset of CN NPM1Mut :FLT3Wt patients with AML have dismal outcomes, suggesting that uncharacterized alterations influence the outcomes in these patients. To address this, we performed reverse phase protein array (RPPA) analysis on CD34+ bone marrow cells isolated from 43 de novo CN NPM1Mut :FLT3Wt AML patient as well as healthy donor controls. Through these analyses, we observed that overexpression of heterogeneous nuclear ribonucleoprotein K (hnRNP K) associated with extremely poor outcomes within this a priori favorable prognostic group, as almost 90% of patients with increased hnRNP K expression died within 12 months of diagnosis while nearly 40% of individuals with normal hnRNP K expression survived seven years (Figure 1A). hnRNP K is a multifunctional RNA and DNA binding protein whose expression is often altered in cancers. To directly examine the functional relationship between hnRNP K overexpression and mutant NPM1 in hematologic malignancies, we generated tissue-specific transgenic mouse models with the ability to overexpress hnRNP K (hnRNP KTg) in the presence or absence of mutant Npm1 (Npm1Tg). By crossing these mice with Vav-Cre expressing mice, we specifically activated hnRNP K overexpression and mutant NPM1 expression in the hematological compartment. Using Lin-CD117+ hematopoietic stem cells (HSCs) from hnRNP KTg, Npm1Tg, and hnRNP KTg;Npm1Tg mice, we observed significant changes in differentiation and proliferation potential in colony formation assays. Overexpression of hnRNP K alone significantly increased the number of colonies compared to wild type and Npm1Tg HSCs while expression of mutant Npm1Tg resulted in increased numbers of cells compared to wild type and hnRNP KTg HSCs. Importantly, the combination of hnRNP K overexpression and mutant Npm1 resulted in a cumulative increase in both the number of colonies and number of cells, indicating that hnRNP K and mutant NPM1 cooperate to dictate differentiation and proliferation potential in HSCs (Figure 1B). Next, we examined the in vivo impact of hnRNP K overexpression and mutant Npm1 expression by analyzing the bone marrows of NpmTg, hnRNP KTg, and Npm1Tg;hnRNP KTg mice. Within the first six months of life, these mice rapidly devel