Highly Restricted Usage of Ig H Chain VH14 Family Gene Segments in Slp65-Deficient Pre-B Cell Leukemia in Mice
Highly Restricted Usage of Ig H Chain VH14 Family Gene Segments in Slp65-Deficient Pre-B Cell Leukemia in Mice
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DOI：
10.4049/jimmunol.1201440
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发表时间：
2012-11
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影响因子：
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通讯作者：
V. Ta;Marjolein J. W. de Bruijn;Louise S. Matheson;M. Zoller;M. P. Bach;H. Wardemann;H. Jumaa;A. Corcoran;R. Hendriks
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作者：
V. Ta;Marjolein J. W. de Bruijn;Louise S. Matheson;M. Zoller;M. P. Bach;H. Wardemann;H. Jumaa;A. Corcoran;R. Hendriks
缺乏衔接蛋白Slp 65（也称为Blnk）的小鼠自发发展前B细胞白血病，Slp 65是BCR（前BCR）信号传导的关键组分。在这些白血病中，增殖被认为是由组成性Jak 3/Stat 5信号传导驱动的，主要是由于IL-7的自分泌产生以及前BCR的高表面表达。在这项研究中，我们调查了特定的IgH特异性是否会使Slp 65缺陷的前B细胞发生恶性转化。尽管VH-D-JH连接是多样的，但我们发现高度限制的IG VH基因使用：60例白血病中有55例（约92%）使用VH 14/SM 7家族基因，主要是VH 14 -1和VH 14 -2。当与替代或常规L链组合时，这些VH 14 IgH链不提供增加的增殖信号或表现出增强的多反应性或自身反应性。因此，我们得出结论，前BCR特异性本身并不有助于致癌转化。值得注意的是，在高比例的Slp 65缺陷型白血病中，未表达的IgH等位基因也具有VH 14家族重排（50个中有10个）或处于种系构型（50个中有10个）。VH 14 -1和VH 14 -2基因区域与其相邻的VH基因不同，它们在Rag 1缺陷小鼠中的pro-B细胞阶段显示活跃的H3 K4 me 3组蛋白修饰标记和生殖系转录。综上所述，这些发现表明，在Slp 65缺陷型小鼠中，恶性转化主要限于特定的前B细胞，所述前B细胞来源于在VH-至D-JH重组时具有限制性IgH VH区可及性的pro-B细胞。
Mice deficient for the adapter protein Slp65 (also known as Blnk), a key component in precursor-BCR (pre-BCR) signaling, spontaneously develop pre-B cell leukemia. In these leukemias, proliferation is thought to be driven by constitutive Jak3/Stat5 signaling, mostly due to autocrine production of IL-7, together with high surface expression of the pre-BCR. In this study, we investigated whether particular IgH specificities would predispose Slp65-deficient pre-B cells to malignant transformation. Whereas VH-D-JH junctions were diverse, we found highly restricted Ig VH gene usage: 55 out of 60 (∼92%) leukemias used a VH14/SM7-family gene, mainly VH14-1 and VH14-2. When combined with surrogate or conventional L chains, these VH14 IgH chains did not provide increased proliferative signals or exhibit enhanced poly- or autoreactivity. We therefore conclude that pre-BCR specificity per se did not contribute to oncogenic transformation. Remarkably, in a high proportion of Slp65-deficient leukemias, the nonexpressed IgH allele also harbored a VH14-family rearrangement (10 out of 50) or was in the germline configuration (10 out of 50). VH14-1 and VH14-2 gene regions differed from their neighboring VH genes in that they showed active H3K4me3 histone modification marks and germline transcription at the pro-B cell stage in Rag1-deficient mice. Taken together, these findings demonstrate that in Slp65-deficient mice, malignant transformation is largely limited to particular pre-B cells that originate from pro-B cells that had restricted IgH VH region accessibility at the time of VH-to D-JH recombination.