Abstract P073: Targeting JAK1 signaling for molecular prevention in clonal hematopoiesis

• Published in: Cancer prevention research (Philadelphia, Pa.) Pa.), 2023-01, Vol.16 (1_Supplement), p.P073-P073
• Main Authors: Vela, Pablo Sánchez, Benitez, Anthony Martinez, Krishnan, Aishwarya, Kleppe, Maria, Cai, Sheng F., Levine, Ross L.
• Format: Article
• Language: English
• ISSN: 1940-6215; 1940-6215
• DOI: 10.1158/1940-6215.PrecPrev22-P073

Myeloid malignancies are characterized by the stepwise acquisition of different somatic mutations in hematopoietic stem and progenitor cells (HSPCs) that promote subsequent leukemic transformation. When these mutations, including in the epigenetic regulator TET2, are found in the blood cells of individuals without any signs of hematologic malignancy, this condition is termed clonal hematopoiesis (CH). The incidence of CH increases with age and has been recognized as a risk factor for the development of secondary heme malignancies and cardiovascular disease. Nonetheless, currently no therapies exist to alter the natural course of CH. Accumulating evidence indicates that inflammatory signals can enhance myeloproliferation of CH HSPCs suggesting a key role of inflammatory stressors in the promotion of the clonal advantage of Tet2-mutant stem cells. However, whether hijacking this inflammatory signaling will prevent clonal expansion and leukemogenesis is currently unknown. The members of the Janus family of nonreceptor tyrosine kinases (JAK) transmit a diversity of ligand-mediated signals and act as a signaling-hub for inflammation. Our central hypothesis is that CH and progression to acute myeloid leukemia (AML) occurs in the setting of inflammatory stress and that mutant clonal expansion is mediated by JAK/STAT inflammatory signaling, primarily through JAK1, a non-essential gene in adult hematopoiesis. We previously showed that Jak1 is critical for stress hematopoiesis in HSPCs. To assess whether Tet2-mediated clonal expansion requires Jak1, signaling, we established a conditional Scl driven Cre-inducible deletion model of Tet2-/- and Jak1-/-. We have adapted a bone marrow derived endothelial cell organoid system that allows to maintain and expand HSPCs during longer periods of time. In this setting Tet2-/- HSPCs show increased sensitivity to IL3, a Jak1-dependent cytokine that mediates exit of quiescence in HSPCs. The loss of competitive advantage of Tet2-/- Jak1-/- cells persists even in the context of co-culture with Jak1-/- Tet2-wildtype cells, and to a lesser extent in the presence of the Jak1 inhibitor Itacitinib, suggesting a denser requirement for Jak1 in CH mutant clones compared to wild-type HSPCs. Ex-vivo colony forming assays and in vivo competitive transplants demonstrate that the self-renewal abilities of Tet2-mutant HSPCs require Jak1 signaling. Furthermore, the extramedullary hematopoiesis observed in a primary model of Tet2-/- pre-leukemic m