• THE ROLE OFNORMAL AND ONCOGENICJANUS KINASE 2 IN HEMATOPOIETIC STEM CELLS

      Mohi, Golam; AKADA, HAJIME (2014)
      During my Ph.D. training, I first experimentally proved that the expression of oncogenic Jak2V617F wassufficient to induce MPNs and transformed only HSCs into CSCs for developing MPNs. Thus, it is criticalto understand the role of both normal and oncogenic Jak2 in HSCs to find the mechanism to cureJak2V617F-positive MPNs. Therefore, I have mainly studied two major questions in Jak2:1) The role of normal Jak2 in hematopoietic stem cells for adult hematopoiesis2) The role of oncogenic form of Jak2, Jak2V617F, in cancer stem cells for MPN developmentFirst question has not been addressed since 1998, because conventional Jak2 knock-out mice wereembryonic lethal. Thus, I hypothesized that Jak2 plays a pivotal role in adult hematopoietic stem cellmaintenance. I successfully prove that Jak2 is the one of key regulators of HSCs. Conditional Jak2 deletionin mice caused an irreversible HSCs impairment. My data strongly suggest that Jak2 plays a critical role inthe maintenance of quiescence, survival and self-renewal of adult HSCs.Second question has been studied after the discovery of a somatic point mutation, Jak2V617F, in a majorityof patients with MPNs in 2005. I hypothesized that this oncogenic mutation confers unique properties inCSCs maintenance for MPNs development. Surprisingly, I found that the site of leukemogenesis shiftedfrom BM to spleen, and spleen became the major source of CSCs for Jak2V617F-positive MPNs. The age-associated progressive expansion of CSCs was seen in spleen. Splenic-CSCs were capable to propagateMPN disease and possessed a greater proliferative advantage than BM-CSCs. The Jak2V617F-CSCsestablished a positive-feedback mechanism with CD169+ macrophage progenitors. Depletion of CD169+macrophage progenitors reduced the number of Jak2V617F-CSCs. Gene profiling revealed that splenic-CSCs have distinct gene expression compared to BM-CSCs. Together, I demonstrated that Jak2V617F-CSCs are maintained in spleen for long-term MPN progression.By utilizing gene analysis data from two projects, I discovered a set of unique genes/pathways regulated byonly Jak2V617F but not by wildtype Jak2. All together, my Ph.D. researches provided the potential genetarget a novel therapy for Jak2V617F-positive MPNs.