Signal transducer and activator of transcription (STAT)5 activation by BCR/ABL is dependent on intact Src homology (SH)3 and SH2 domains of BCR/ABL and is required for leukemogenesis.
Signal transducer and activator of transcription (STAT)5 activation by BCR/ABL is dependent on intact Src homology (SH)3 and SH2 domains of BCR/ABL and is required for leukemogenesis.
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DOI：
10.1084/jem.189.8.1229
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发表时间：
1999-04-19
影响因子：
15.3
通讯作者：
Skorski, T
中科院分区：
文献类型：
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作者：
Nieborowska-Skorska, M;Wasik, M A;Slupianek, A;Salomoni, P;Kitamura, T;Calabretta, B;Skorski, T
信号换能器和转录激活因子（STAT）5在表达BCR/ abl的细胞中被组成性激活，但这种激活的机制和功能后果尚不清楚。我们在这里表明，BCR/ABL通过一种机制诱导STAT5的磷酸化和激活，该机制需要BCR/ABL Src同源性（SH）2结构域和富含脯氨酸的SH3结构域结合位点。STAT5激活缺陷BCR/ABL SH3+SH2结构域突变体在32Dcl3生长因子依赖的骨髓前细胞中表达后，具有酪氨酸激酶和激活Ras的功能，但不能保护白细胞介素3和/或血清退出诱导的细胞凋亡，也不能诱导严重联合免疫缺陷小鼠白血病。在互补实验中，在转染STAT5激活缺陷BCR/ABL SH3+SH2突变体的32Dcl3细胞中，表达显性活性STAT5B突变体（STAT5B- dam），而非野生型STAT5B突变体（STAT5B- wt），恢复了对凋亡的保护，刺激了生长因子不依赖的细胞周期进程，并恢复了小鼠的白血病发生潜能。此外，在转染野生型BCR/ABL的32Dcl3细胞中，表达显性阴性STAT5B突变体（STAT5B- dnm）可抑制这些细胞的凋亡抵抗、生长因子非依赖性增殖和白血病潜能。在逆转录病毒感染的小鼠骨髓细胞中，STAT5B-DNM的表达抑制BCR/ abl依赖性转化。此外，STAT5B-DAM，而不是STAT5B-WT，显著增强STAT5激活缺陷的BCR/ABL SH3+SH2突变体诱导小鼠原代骨髓祖细胞不依赖生长因子集落形成的能力。然而，STAT5B-DAM并不能挽救激酶缺陷的K1172R BCR/ABL或三重突变体Y177F+R522L+ Y793F BCR/ABL的生长因子独立集落形成，两者也不能激活STAT5。总之，这些数据表明，BCR/ABL激活STAT5依赖于来自多个域的信号，并记录了STAT5调控的途径在BCR/ABL白血病发生中的重要作用。
Signal transducer and activator of transcription (STAT)5 is constitutively activated in BCR/ ABL-expressing cells, but the mechanisms and functional consequences of such activation are unknown. We show here that BCR/ABL induces phosphorylation and activation of STAT5 by a mechanism that requires the BCR/ABL Src homology (SH)2 domain and the proline-rich binding site of the SH3 domain. Upon expression in 32Dcl3 growth factor–dependent myeloid precursor cells, STAT5 activation–deficient BCR/ABL SH3+SH2 domain mutants functioned as tyrosine kinase and activated Ras, but failed to protect from apoptosis induced by withdrawal of interleukin 3 and/or serum and did not induce leukemia in severe combined immunodeficiency mice. In complementation assays, expression of a dominant-active STAT5B mutant (STAT5B-DAM), but not wild-type STAT5B (STAT5B-WT), in 32Dcl3 cells transfected with STAT5 activation–deficient BCR/ABL SH3+SH2 mutants restored protection from apoptosis, stimulated growth factor–independent cell cycle progression, and rescued the leukemogenic potential in mice. Moreover, expression of a dominant-negative STAT5B mutant (STAT5B-DNM) in 32Dcl3 cells transfected with wild-type BCR/ABL inhibited apoptosis resistance, growth factor–independent proliferation, and the leukemogenic potential of these cells. In retrovirally infected mouse bone marrow cells, expression of STAT5B-DNM inhibited BCR/ABL-dependent transformation. Moreover, STAT5B-DAM, but not STAT5B-WT, markedly enhanced the ability of STAT5 activation–defective BCR/ABL SH3+SH2 mutants to induce growth factor–independent colony formation of primary mouse bone marrow progenitor cells. However, STAT5B-DAM did not rescue the growth factor–independent colony formation of kinase-deficient K1172R BCR/ABL or the triple mutant Y177F+R522L+ Y793F BCR/ABL, both of which also fail to activate STAT5. Together, these data demonstrate that STAT5 activation by BCR/ABL is dependent on signaling from more than one domain and document the important role of STAT5-regulated pathways in BCR/ABL leukemogenesis.