BCR-ABL but not JAK2 V617F inhibits erythropoiesis through the Ras signal by inducing p21CIP1/WAF1.
BCR-ABL is a causative tyrosine kinase (TK) of chronic myelogenous leukemia (CML). In CML patients, although myeloid cells are remarkably proliferating, erythroid cells are rather decreased and anemia is commonly observed. This phenotype is quite different from that observed in polycythemia vera (PV) caused by JAK2 V617F, whereas both oncogenic TKs activate common downstream molecules at the level of hematopoietic stem cells (HSCs). To clarify this mechanism, we investigated the effects of BCR-ABL and JAK2 V617F on erythropoiesis. Enforced expression of BCR-ABL but not of JAK2 V617F in murine LSK (Lineage(-)Sca-1(hi)CD117(hi)) cells inhibited the development of erythroid cells. Among several signaling molecules downstream of BCR-ABL, an active mutant of N-Ras (N-RasE12) but not of STAT5 or phosphatidylinositol 3-kinase (PI3-K) inhibited erythropoiesis, while N-RasE12 enhanced the development of myeloid cells. BCR-ABL activated Ras signal more intensely than JAK2 V617F, and inhibition of Ras by manumycin A, a farnesyltransferase inhibitor, ameliorated erythroid colony formation of CML cells. As for the mechanisms of Ras-induced suppression of erythropoiesis, we found that GATA-1, an erythroid-specific transcription factor, blocked Ras-mediated mitogenic signaling at the level of MEK through the direct interaction. Furthermore, enforced expression of N-RasE12 in LSK cells derived from p53-, p16(INK4a)/p19(ARF)-, and p21(CIP1/WAF1)-null/wild-type mice revealed that suppressed erythroid cell growth by N-RasE12 was restored only by p21(CIP1/WAF1) deficiency, indicating that a cyclin-dependent kinase (CDK) inhibitor, p21(CIP1/WAF1), plays crucial roles in Ras-induced suppression of erythropoiesis. These data would, at least partly, explain why respective oncogenic TKs cause different disease phenotypes.
Tokunaga
Masahiro
M
Department of Hematology and Oncology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, USA.
Ezoe
Sachiko
S
Tanaka
Hirokazu
H
Satoh
Yusuke
Y
Fukushima
Kentaro
K
Matsui
Keiko
K
Shibata
Masaru
M
Tanimura
Akira
A
Oritani
Kenji
K
Matsumura
Itaru
I
Kanakura
Yuzuru
Y
D019943:Amino Acid Substitution; D000818:Animals; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004920:Erythropoiesis; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D022423:Myeloid Cells / Q000378:metabolism; D041681:NIH 3T3 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011090:Polyenes / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
C493957:Cdkn1a protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D050799:STAT5 Transcription Factor; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D020930:MAP Kinase Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); C054474:manumycin