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 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.
Ghaffari
S
S
Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Kitidis
C
C
Fleming
M D
MD
Neubauer
H
H
Pfeffer
K
K
Lodish
H F
HF
D019943:Amino Acid Substitution; D000740:Anemia / Q000097:blood / Q000196:embryology / Q000235:genetics / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation; D018274:Electroporation; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004920:Erythropoiesis / Q000235:genetics / Q000502:physiology*; D005313:Fetal Death / Q000209:etiology; D005315:Fetal Diseases / Q000097:blood / Q000235:genetics / Q000473:pathology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology*; D005865:Gestational Age; D016298:Hematopoietic Cell Growth Factors / Q000502:physiology; D053614:Janus Kinase 2; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology; D008099:Liver / Q000196:embryology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins; D017467:Receptors, Erythropoietin / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects
D016298:Hematopoietic Cell Growth Factors; D011518:Proto-Oncogene Proteins; D017467:Receptors, Erythropoietin; D011993:Recombinant Fusion Proteins; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2