Erythropoiesis in the absence of janus-kinase 2: BCR-ABL induces red cell formation in JAK2(-/-) hematopoietic progenitors

The receptor-associated protein tyrosine kinase janus-kinase 2 (JAK2) is es sential for normal red cell development and for erythropoietin receptor (Ep oR) signaling. JAK2(-/-) embryos are severely deficient in erythropoiesis a nd die at an early stage of development from fetal anemia. The binding of e rythropoietin (Epo) to the EpoR triggers the activation of JAK2, the phosph orylation of the EpoR, and the initiation of the EpoR signaling cascade. In addition to Epo binding to its receptor, signaling pathways downstream of the EpoR can also be stimulated by the BCR-ABL oncoprotein. This study expl ored whether JAK2 is required for BCR-ABL-mediated stimulation of erythropo iesis. Here, it is shown that JAK2 is constitutively tyrosine phosphorylate d in cultured and primary erythroid cells expressing BCR-ABL. However, BCR- ABL effectively supports normal erythroid proliferation, differentiation, a nd maturation in JAK2-deficient fetal liver cells. Using mutants of SCR-ABL , this study shows that certain signaling pathways activated by BCR-ABL seg ments distinct from its tyrosine kinase domain are essential for rescue of erythropoiesis in JAK2(-/-) progenitors. The consequences of these multiple signaling pathways for normal erythroid development are discussed. (C) 200 1 by The American Society of Hematology.