VISION vol.24
【VISION 最新・血液内科シリーズvol.24 私と仲間たち】


Our basic research goal is to understand the pathophysiology of the classical Philadelphia-negative myeloproliferative neoplasms (MPN) including polycythemia vera (PV), essential thrombocythemia(ET) and primary myelofibrosis (PMF).  

In recent years , the tremendous outstanding progress had been achieved in this fields, especially in the molecular-genetics of MPN. In contrast, we are focusing on the role of the microenvironment in MPN pathogenesis. We have found that physiological elements in bone marrow microenvironment i.e. oxygen levels, glucose availability and pH affected the development of MPN.

First, we revealed that hypoxic conditions ( 1% oxygen levels) suppressed the growth of MPN cells containing oncogenic kinase, known as JAK2V617F mutant. (1)In addition, activity of JAK2V617F was decreased at hypoxia. Our works also revealed that elevation of reactive oxygen species had central roles in the process through inhibiting SH-2 domain containing protein phosphatase (SHP-2). (1)Based on these findings, we investigated the role of SHP-2 in MPN and found that SHP-2 is aberrantly activated in MPN cells and inhibition of SHP-2 either by chemical inhibitor or gene -knockdown, suppressed the growth of MPN cells.

We also revealed that AMPK, which works as sensor for intracellular glucose and ATP levels, could block the action of JAK2V617F through activation of protein tyrosine phosphatase PP2A. (2) (3)We found that Metformin, one of the most popular medicine for the treatment of diabetes mellitus, activated AMPK leading to the suppression of JAK2V617F function. Interestingly, metformin enhanced the anti-leukemic activity of ruxolitinib, a potent JAK1/JAK2 inhibitor, recently approved for the treatment of MPN in many countries including Europe, United states and also in Japan. Together with these findings, we are trying to establish new therapeutic strategies for classical Philadelphia-negative MPN.

                      (Schematic model of our research for MPN biology)