Targeting jak1 signaling for molecular prevention in clonal hematopoiesis

Myeloid malignancies are characterized by the stepwise acquisition of somatic mutations in hematopoietic stem and progenitor cells (HSPCs) that promote subsequent leukemic transformation. This condition, termed clonal hematopoiesis (CH), has been recognized as a risk factor for the development of secondary heme malignancies and cardiovascular disease. Accumulating evidence indicates that inflammatory stressors can enhance myeloproliferation of mutant HSPCs. However, whether hijacking this inflammatory signaling will prevent clonal expansion and leukemogenesis is currently unknown. Our central hypothesis is that TET2-mutant CH progression to acute myeloid leukemia (AML) occurs in the setting of inflammatory stress mediated by JAK1, which acts as a signaling-hub for inflammation. To assess whether Tet2-mediated clonal expansion requires Jak1 signaling, we established a conditional Scl driven Cre-inducible deletion model of Tet2-/- and Jak1-/-. In this setting Tet2-/- HSPCs show increased sensitivity to IL3, a Jak1-dependent cytokine that mediates stress hematopoiesis and exit of quiescence. The loss of competitive advantage of Tet2-/- Jak1-/- cells persists even in the context of co-culture with Jak1-/-Tet2-wildtype cells, suggesting a denser requirement for Jak1 in CH mutant clones compared to wild-type HSPCs. 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 myeloproliferation, was also dependent on Jak1. Moreover, studies in AML models showed that pharmacologic Jak1 inhibition abrogated ex vivo colony formation. In summary, targeting JAK1 mediated inflammatory signaling in CH-mutant HSPCs has the ability to translate into a precision interception strategy aimed at preventing clonal expansion. Myeloid malignancies are characterized by the stepwise acquisition of somatic mutations in hematopoietic stem and progenitor cells (HSPCs) that promote subsequent leukemic transformation. This condition, termed clonal hematopoiesis (CH), has been recognized as a risk factor for the development of secondary heme malignancies and cardiovascular disease. Accumulating evidence indicates that inflammatory stressors can enhance myeloproliferation of mutant HSPCs. However, whether hijacking this inflammatory signaling will prevent clonal expansion and leukemogenesis is currently unknown. Our central hypothesis is that TET2-mutant CH progression to acute myeloid leukemia (AML) occurs in the setting of inflammatory stress mediated by JAK1, which acts as a signaling-hub for inflammation. To assess whether Tet2-mediated clonal expansion requires Jak1 signaling, we established a conditional Scl driven Cre-inducible deletion model of Tet2-/- and Jak1-/-. In this setting Tet2-/- HSPCs show increased sensitivity to IL3, a Jak1-dependent cytokine that mediates stress hematopoiesis and exit of quiescence. The loss of competitive advantage of Tet2-/- Jak1-/- cells persists even in the context of co-culture with Jak1-/-Tet2-wildtype cells, suggesting a denser requirement for Jak1 in CH mutant clones compared to wild-type HSPCs. 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 myeloproliferation, was also dependent on Jak1. Moreover, studies in AML models showed that pharmacologic Jak1 inhibition abrogated ex vivo colony formation. In summary, targeting JAK1 mediated inflammatory signaling in CH-mutant HSPCs has the ability to translate into a precision interception strategy aimed at preventing clonal expansion.