Our research identified HNRNPK as the tumor suppressor responsible for del9q acute myeloid leukemia (AML). We developed multiple model systems, including haploinsufficient (del9q) models, RNA binding mutant (KH-mutations) models, transgenic mice, mouse embryo fibroblast lines, inducible cell lines with altered hnRNP K expression, and cell lines with hnRNP K RNA binding mutations to understand the biological effects of HNRNPK loss in AML. These models enabled us to study how hnRNP K affects protein translation and ribogenesis, two critical processes for cell growth and proliferation. We hypothesize that HNRNPK haploinsufficiency causes abnormal ribogenesis and protein translation defects, re...

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Our research identified HNRNPK as the tumor suppressor responsible for del9q acute myeloid leukemia (AML). We developed multiple model systems, including haploinsufficient (del9q) models, RNA binding mutant (KH-mutations) models, transgenic mice, mouse embryo fibroblast lines, inducible cell lines with altered hnRNP K expression, and cell lines with hnRNP K RNA binding mutations to understand the biological effects of HNRNPK loss in AML. These models enabled us to study how hnRNP K affects protein translation and ribogenesis, two critical processes for cell growth and proliferation. We hypothesize that HNRNPK haploinsufficiency causes abnormal ribogenesis and protein translation defects, revealing potential therapeutic opportunities to induce synthetic lethality in cancer cells. To test this, we will: Determine how HNRNPK loss (and loss of function mutations) impact protein translation and ribogenesis, providing insight into the mechanisms associated with reduced hnRNP K levels. Evaluate the response of HNRNPK haploinsufficient cells to translational inhibitors, assessing their potential as targeted therapies. Develop methods to induce synthetic lethality in AML cells with del9q and in mouse model systems. This research will advance our understanding of how hnRNP K impacts essential biological pathways and develop therapies to induce synthetic lethality in the context of HNRNPK loss. This research will develop potentially therapeutic strategies for AML patients with del9q alterations, HNRNPK haploinsufficiency, and HNRNPK mutations.

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