Analysis of Clinical, Laboratory and Bone Marrow Features in Dominant TPO, MPL and JAK2 Germline Mutated Hereditary Essential Thrombocythemia (HET) Versus Acquired MPL515, CALR and JAK2V617F Mutated ET in Myeloproliferative Neoplasms

Abstract

Evidence for a decisive role of upregulated TPO in ET became available in the 1990s from observations in mice overexpressing a TPO transgene where increased TPO production resulted in a fatal myeloproliferative disorder [1]. High dose exposure to TPO in lethally irradiated mice grafted with bone marrow cells infected with a retrovirus carrying the murin TPO cDNA (TPO high mice) developed a lethal myeloproliferative disorder of TPO induced megakaryocytic granulocytic myeloproliferation with reduced erythropoiesis in the spleen and bone marrow [2]. Normal wild type mice Heterozygous germline gain of function mutation in the TPO gene induces increased levels of plasma TPO as the cause of dominant hereditary essential thrombocythemia (HET) in two families. Gain of function mutations of the Thrombopoietine (TPO) receptor/myeloproliferative leukemia (MPL) receptor in congenital dominant MPL S205N mutated HET and acquired MPL 515 mutated ET are driver causes of normocellular ET without features of PV. The clinical spectrum of acquired JAK2 V617F mutated ET patients is featured by by loose clustered pleiomorphic megakaryocytes in normocellular bone marrow with local increase of erythropiesis, spontaneous endogenous erythroid colony formation (EEC), increased leukocyte alkaline phohatase (LAP) score and low serum EPO levels consistent with prodromal PV. Each of the three variants of dominant heterozygous germline JAK2 V617I , JAK2 R564Q and JAK2 H608N mutated HET does induce cytokine hyperresponsiveness of the hematopoietic progenitor cells to TPO as the cause HET phenotype in blood and bone marrow with normal EEC, plasma TPO and serum EPO levels indicating the absence of PV features. EEC, LAP score and serum EPO levels are normal in MPL and CALR mutated ET and in TPO and JAK2 germline mutated HET patients. Dominant TPO, MPL and JAK2 germline mutated HET, acquired JAK2 V617F ET and MPL 515 mutated ET patients present with aspirin responsive ErythromelalgicThrombotic Thrombocythemia (ETT) as a novel platelet microvascular thrombophilia in thrombocythemia at platelet count between 400 to 1000x10 9 /L or above. ETT was not recorded in CALR mutated ET at platelet counts between 400 and 1000x10 9 /L. respond to TPO treatment by increasing the number of platelets in the circulation and megakaryocytes in the spleen at day 7 to 10 and returned to pretreatment values at day 14 [3]. TPO treatment increased platelet counts 2.3 fold and increased number of megakaryocytes and CFU-Mks. TPO treatment had profound effects on the change of normal into large sized immature megakaryocyte morphology in wild type mice. TPO treatment of wild type mice induced decreased GATA-1 content in megakaryocytes followed by myelofibrosis associated with high levels of transforming growth factor beta-1 (TGG-Beta -1 ) expression in bone marrow and spleen