BCR-ABL but Not JAK2 V617F Inhibits Erythropoiesis through the Ras Signal by Inducing p21CIP1/WAF1*
BCR-ABL but Not JAK2 V617F Inhibits Erythropoiesis through the Ras Signal by Inducing p21CIP1/WAF1*
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DOI：
10.1074/jbc.m110.118653
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发表时间：
2010-07
期刊：
影响因子：
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通讯作者：
M. Tokunaga;S. Ezoe;Hirokazu Tanaka;Yusuke Satoh;K. Fukushima;K. Matsui;Masaru Shibata;Akira Tanimura;K. Oritani;I. Matsumura;Y. Kanakura
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文献类型：
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作者：
M. Tokunaga;S. Ezoe;Hirokazu Tanaka;Yusuke Satoh;K. Fukushima;K. Matsui;Masaru Shibata;Akira Tanimura;K. Oritani;I. Matsumura;Y. Kanakura
BCR-ABL是慢性粒细胞白血病（CML）的一种致病性酪氨酸激酶（TK）。在CML患者中，虽然髓系细胞显著增殖，但红系细胞相当减少，并且通常观察到贫血。这种表型与JAK 2 V617 F引起的真性红细胞增多症（PV）中观察到的表型完全不同，而两种致癌TK均在造血干细胞（HSC）水平上激活共同的下游分子。为了阐明这一机制，我们研究了BCR-ABL和JAK 2 V617 F对红细胞生成的影响。在小鼠LSK（Lineage−Sca-1hiCD 117 hi）细胞中，BCR-ABL而非JAK 2 V617 F的增强表达抑制了红系细胞的发育。在BCR-ABL下游的几种信号分子中，N-Ras（N-RasE 12）的活性突变体（而不是STAT 5或磷脂酰肌醇3-激酶（PI 3-K））抑制红细胞生成，而N-RasE 12促进骨髓细胞的发育。BCR-ABL比JAK 2 V617 F更强烈地激活Ras信号，并且通过法尼基转移酶抑制剂manumycin A抑制Ras，改善CML细胞的红系集落形成。至于Ras抑制红细胞生成的机制，我们发现红细胞特异性转录因子加塔-1通过直接作用在MEK水平阻断Ras介导的促有丝分裂信号。此外，N-RasE 12在来自p53-、p16 INK 4a/p19 ARF-和p21 CIP 1/WAF 1-null/野生型小鼠的LSK细胞中的强制表达揭示，N-RasE 12抑制的红系细胞生长仅通过p21 CIP 1/WAF 1缺陷恢复，表明细胞周期蛋白依赖性激酶（CDK）抑制剂p21 CIP 1/WAF 1在Ras诱导的红细胞生成抑制中起关键作用。这些数据将至少部分地解释为什么各自的致癌TK引起不同的疾病表型。
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-1hiCD117hi) 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-, p16INK4a/p19ARF-, and p21CIP1/WAF1-null/wild-type mice revealed that suppressed erythroid cell growth by N-RasE12 was restored only by p21CIP1/WAF1 deficiency, indicating that a cyclin-dependent kinase (CDK) inhibitor, p21CIP1/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.