• A TUMOR SUPPRESSOR FUNCTION FOR PTPN1 IN MYELOPROLIFERATIVE NEOPLASMS

      Mohi, Golam; JOBE, FATOUMATA (2016)
      Myeloproliferative neoplasms (MPNs) are a class of clonally-derived hematologic malignancies characterized by uncontrolled proliferation of myeloid lineage cells. Theyare classified into Philadelphiachromosome-positive (Ph+)MPNs, consisting of chronic myelogenous leukemia (CML), and Philadelphiachromosome-negative (Ph-)MPNs, consisting of polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis(PMF).The JAK2V617F mutation is the most common abnormality in Ph-MPNs, occurring in ~95% of PV patients, 55% of ET patients and 65% of PMF patients. JAK2V617F mutation results in constitutive activation of the JAK2 tyrosine kinase. Deletion of chromosome 20q (20q-) is a common chromosomal abnormality in myeloid neoplasms, including about 24%of MFcases. The 20q-lesion can coexist with JAK2V617Fmutation in MPN and MDS/MPN. The PTPN1gene is located on human chromosome 20q, within the commonly deleted region. PTPN1 is a tyrosine phosphatase and a known negative regulator of JAK-STAT signaling. The role of PTPN1 loss in the pathogenesis of MPNs and the mechanism by which loss of PTPN1 might contribute to various MPN phenotypes remains elusive. The goalsof this dissertation were to determine the effects of PTPN1 deficiency alone and in JAK2V617F-induced MPNs in vivo. To determine the mechanism by which PTPN1 mediates its tumor suppressor function using hematopoietic cells andassessment of PTPN1 status in 20q-MPN patients.Using conditional knock-out PTPN1 mouse model, we show that deletion of PTPN1 causes an MPN-like phenotype, characterized by increased WBC and NE counts and splenomegaly, compared to control mice. We also show that loss of PTPN1 causesfibrosis in older mice. PTPN1 knockdown significantly increased cell proliferation and activation of JAK2, MAPK and AKT signaling, whereas over expression in JAK2V617F-expressing cells attenuated cytokine-independent cell proliferation and signaling. Our data revealed a cooperative effect between PTPN1 deficiency and JAK2V617F expression in mice as shown by enhanced severity of theMPN phenotype and transformation to MF. Cell autonomous BMT revealed that the effects of PTPN1 deficiency are cell autonomous.Taken together, our results suggest a novel tumor suppressor function for PTPN1 in MPNs.