Glucose Transport Dependency Defines a Therapeutic Vulnerability in Myeloproliferative Neoplasms

Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) comprise a heterogenous group of hematologic malignancies that include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The most prevalent driver mutation, JAK2V617F, is present in over 90% of PV and approximately 60% of ET and PMF cases. Current therapeutic strategies rely on cytoreductive approaches that mitigate disease burden and thromboembolic risk but are not curative. Allogeneic stem cell transplantation remains the only curative option, underscoring the need for novel therapeutic strategies. We previously identified hypoxia–inducible factor 1 (HIF-‍‍1) as a selective vulnerability in JAK2V617F–positive cells, but the underlying metabolic mechanisms remain incompletely defined. CRISPR-Cas9 knockout clones targeting the HIF-1–regulated glucose transporters GLUT1 and GLUT3 were generated in Jak2WT and Jak2V617F backgrounds to charaterize glucose uptake depletion by RNA sequencing.