TREATMENT OF MYELOPROLIFERATIVE DISORDERS WITH ADAPTOR PROTEIN LNK

摘要

Janus kinase 2 (JAK2) associates with cytokine receptors and is essential for signal transduction in hematopoietic cells. The JAK2 mutation, JAK2 V617F, prevalent in myeloproliferative disorders, confers cytokine-independent proliferation and constitutive activation of downstream signaling pathways, when co-expressed with homodimeric type I cytokine receptors. The adaptor protein LnK is a negative regulator of hematopoietic cytokine receptors, including EPOR and MPL. LnK attenuates wild type JAK2 signaling in hematopoietic Ba/F3 cells expressing MPL. LnK also inhibits cytokine-independent growth and signaling conferred by JAK2 V617F in those cells. LnK, via its SH2 domain, PH domain, and other regions, associates with JAK2 and JAK2 V617F. Additional LnK domains are involved in LnK downregulation of JAK2 V617F constitutive activation. Elucidating the pathways that attenuate JAK2 and JAK2 V617F signaling provides insight into myeloproliferative disorders and helps to develop therapeutic approaches. Inhibition of Lnk enhances the expression of hematopoetic stem cells and hematopoetic progenitor cells.