Acquisition of JAK2, PTPN11, and RAS mutations during disease progression in primary myelodysplastic syndrome

Cytokines play an important role in the developmental programs of normal hematopoiesis and leukemia. Signaling through cytokines receptors is mediated in part by the activation of tyrosine kinases, particularly the Janus kinases (Jaks). Many of the effects of Jak2 are mediated through the recruitment of signal transducer and activator of transcription (Stat) to phosphotyrosyl residues on the erythropoietin, granulocyte macrophage colony-stimulating factor, and interleukin-3 receptors. Shp2, the nonreceptor tyrosine phosphatase encoded by PTPN11, also participates in signaling events downstream of the receptors of growth factors, cytokines, hormones, antigens, and extracellular matrixes. It has compound functions and is involved in a variety of signal transduction processes, such as the Ras-Raf-Map kinase, Jak-Stat, PI3 kinase, and nuclear factor-B (NF-B) pathways. Jak2 and Shp2 form a complex signaling network in hematopoietic progenitor cells. Perturbed Jak2 and Shp2 signalings may induce hematopoietic malignancies. Recently, a somatic point mutation of JAK2 (V617F), which results in constitutive activation of the tyrosine kinase and factor independent growth of hematopoietic cells, has been found in patients with myeloproliferative disorders.1 Dominant mutations in PTPN11, which result in gain of function of shp2, have also been demonstrated in juvenile myelomonocytic leukemia (JMML).2