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Blood, 15 November 2001, Vol. 98, No. 10, pp. 2948-2957
HEMATOPOIESIS
Erythropoiesis in the absence of janus-kinase 2: BCR-ABL
induces red cell formation in JAK2 / hematopoietic
progenitors
Saghi Ghaffari,
Claire Kitidis,
Mark D. Fleming,
Hans Neubauer,
Klaus Pfeffer, and
Harvey F. Lodish
From the Whitehead Institute for Biomedical Research
and Massachusetts Institute of Technology, Cambridge, MA; Departments
of Pathology, Children's Hospital and Harvard Medical School, Boston,
MA; Technical University of Munich, Munich, Germany.
The receptor-associated protein tyrosine kinase janus-kinase 2 (JAK2) is essential for normal red cell development and for erythropoietin receptor (EpoR) signaling. JAK2 / embryos
are severely deficient in erythropoiesis and die at an early stage of
development from fetal anemia. The binding of erythropoietin (Epo) to
the EpoR triggers the activation of JAK2, the phosphorylation 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 explored whether JAK2 is required for BCR-ABL-mediated stimulation of erythropoiesis. Here, it is shown that JAK2 is constitutively tyrosine phosphorylated in cultured and
primary erythroid cells expressing BCR-ABL. However, BCR-ABL
effectively supports normal erythroid proliferation, differentiation,
and maturation in JAK2-deficient fetal liver cells. Using mutants of
BCR-ABL, this study shows that certain signaling pathways activated by
BCR-ABL segments 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.
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