トリプルネガティブ本態性血小板血症の臨床的・分子生物学的特徴

抄録

Essential thrombocythemia (ET), a subgroup of Philadelphia chromosome-negative myeloproliferative neoplasms, is a hematopoietic neoplasm characterized by thrombocytosis. Identifi cation of JAK2, MPL, and CALR mutations as disease-specifi c driver gene mutations improved the understanding of the molecular pathology of the disease. However, a subset of patients is negative for these mutations, a condition defi ned as triple-negative ET (TN-ET). According to a series of cohort studies in different countries, including ours, TN-ET predominantly occurs in young women, who show lower incidences of progression to bone marrow fi brosis and leukemia than in those with ET harboring the driver mutations. Notably, no such transformation event was observed in our Japanese cohort. Although whole-exome sequencing analysis of patients with TN-ET identifi ed non-canonical mutations in JAK2 or MPL in a subset of patients, these mutant proteins do not possess strong oncogenic capacity. Furthermore, most patients with TN-ET harbored no somatic mutation and presented with polyclonal hematopoiesis, indicating that reactive thrombocytosis occurred in TN-ET. Conversely, the levels of cytokines that promote platelet production in the serum showed no significant difference between patients with TN-ET and healthy volunteers. Moreover, hematopoietic stem/progenitor cells of TNET could form megakaryocytic colonies in a cell-autonomous manner. These fi ndings suggest that, hematopoietic stem/progenitor cells in TN-ET have acquired the ability to promote cell-autonomous megakaryopoiesis without acquiring somatic mutations, leading to the development of thrombocytosis. Essential thrombocythemia (ET), a subgroup of Philadelphia chromosome-negative myeloproliferative neoplasms, is a hematopoietic neoplasm characterized by thrombocytosis. Identifi cation of JAK2, MPL, and CALR mutations as disease-specifi c driver gene mutations improved the understanding of the molecular pathology of the disease. However, a subset of patients is negative for these mutations, a condition defi ned as triple-negative ET (TN-ET). According to a series of cohort studies in different countries, including ours, TN-ET predominantly occurs in young women, who show lower incidences of progression to bone marrow fi brosis and leukemia than in those with ET harboring the driver mutations. Notably, no such transformation event was observed in our Japanese cohort. Although whole-exome sequencing analysis of patients with TN-ET identifi ed non-canonical mutations in JAK2 or MPL in a subset of patients, these mutant proteins do not possess strong oncogenic capacity. Furthermore, most patients with TN-ET harbored no somatic mutation and presented with polyclonal hematopoiesis, indicating that reactive thrombocytosis occurred in TN-ET. Conversely, the levels of cytokines that promote platelet production in the serum showed no significant difference between patients with TN-ET and healthy volunteers. Moreover, hematopoietic stem/progenitor cells of TNET could form megakaryocytic colonies in a cell-autonomous manner. These fi ndings suggest that, hematopoietic stem/progenitor cells in TN-ET have acquired the ability to promote cell-autonomous megakaryopoiesis without acquiring somatic mutations, leading to the development of thrombocytosis.