Hnrnpk haploinsufficiency in del(9q) Acute Myeloid Leukemia reveals targetable vulnerabilities Free

Deletion of the long arm of chromosome 9, del(9q), is a recurrent cytogenetic abnormality in AML and encompasses the HNRNPK locus at 9q21.32. hnRNP K is a multifunctional RNA- and DNA-binding protein involved in chromatin remodeling, transcriptional regulation, and RNA metabolism. Monoallelic deletions or loss-of-function mutations in HNRNPK, collectively observed in ~5–6% of AML cases, directly contribute to leukemogenesis.

We previously showed that Hnrnpk haploinsufficiency disrupts p53 and myeloid lineage-specifying pathways (e.g., C/EBPα and PU.1), impairing differentiation and expanding myeloid progenitors—recapitulating del(9q) AML features. While elucidating these pathways has aided our understanding of AML biology, they remain largely undruggable. Therefore, identifying alternative, targetable vulnerabilities in HNRNPK-deficient AML is of significant clinical interest. To this end, our current studies reveal that HNRNPK-deficient cells exhibit marked sensitivity to translational inhibition, indicating a synthetic lethal interaction driven by impaired protein synthesis.

To delineate the molecular basis of this vulnerability, we used RIP-seq, proteomics (RPPA, IP-MS), and translational profiling. Here, we identified that HNRNPK deficiency caused dysregulated mTOR signaling, aberrant ribosomal protein S6 phosphorylation, and altered expression of key translation initiation/elongation factors. Critically, rRNA processing was impaired, disrupting 47S precursor maturation and leading to defective 40S and 60S subunit assembly and reduced active polysomes—suggesting that del(9q) AML may represent a novel ribosomopathy.

Importantly, complete HNRNPK loss is embryonically lethal, and large-scale CRISPR datasets identify it as essential, underscoring its dosage sensitivity and potential for synthetic lethal therapeutic strategies. To uncover synthetic lethal interactions, we performed a genome-wide CRISPR-Cas9 dropout screen in HNRNPK-deficient cells, identifying dependencies in ribosome biogenesis, translation initiation, and metabolite synthesis as potential vulnerabilities. We are currently using primary cells harboring HNRNPK deletions and genetically engineered models with reduced hnRNP K expression to identify therapies that induce cell death in an hnRNP K-dependent manner.

Collectively, our findings establish hnRNP K as a dosage-sensitive tumor suppressor and suggest del(9q) AML as a novel ribosomopathy. Moreover, the synthetic vulnerabilities identified in our study provide a strong rationale for developing targeted therapies that exploit HNRNPK haploinsufficiency and lay the foundation for the clinical development of agents that induce synthetic lethality in this subset of patients with AML.