Disruption of the multiple tumor suppressor gene MTS1/p16(INK4a)/CDKN2 by illegitimate V(D)J recombinase activity in T-cell acute lymphoblastic leukemias
Disruption of the multiple tumor suppressor gene MTS1/p16(INK4a)/CDKN2 by illegitimate V(D)J recombinase activity in T-cell acute lymphoblastic leukemias
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DOI：
10.1182/blood.v90.9.3720
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发表时间：
1997-11-01
期刊：
影响因子：
20.3
通讯作者：
Sigaux, F
中科院分区：
文献类型：
--
作者：
Cayuela, JM;Gardie, B;Sigaux, F
我们最近发现，编码p16(INK4a)和p19(ARF)细胞周期抑制因子的多肿瘤抑制基因1(MTS1)在大多数人类T细胞急性淋巴细胞白血病(T-ALL)中被缺失或中断而失活，这是迄今为止在这种疾病中描述的最常见的遗传事件。为了分析这些染色体事件的机制，我们使用克隆、测序和/或聚合酶链式反应图谱来研究MTS1基因座上发生的15个重排。我们发现，这些断点出现在两个集群(MTS1(BCRα)和MTS1(BCR Beta))中。MTS1(BCRα)发生的3个重排对应于5‘MTS2外显子1和5’MTS1外显子1α序列的反复重组，MTS1(BCRβ)内12个重排中的10个重排的断裂点位于一个多态(CA)重复序列，提示该序列可能在聚集性中起作用。对MTS1(BCRα)和MTS1(BCRβ)的序列分析和PGR作图实验表明，紧密聚集的断裂点位于七聚体附近，其序列与V(D)J重组所涉及的序列相似。此外，所有病例中都存在短的缺失、富含GC的随机核苷酸添加和克隆特异的连接序列，进一步表明重排是由于不合理的TR(D)J重组酶活性，这些数据首次证明了肿瘤抑制基因可以通过V(D)J重组机制失活。此外，他们强化了这样的观点，即这一过程通常是T细胞分化所必需的，在T-ALL的发病机制中起着至关重要的作用。(C)1997年由美国血液病学会主办。
We have recently shown that the multiple tumor suppressor gene 1 (MTS1) encoding the p16(INK4a) and p19(ARF) cell-cycle inhibitors is inactivated by deletion or disruption in most human T-cell acute lymphoblastic leukemias (T-ALLs), representing the most frequent genetic event thus far described in this disease, To analyze the mechanism of these chromosomal events, we used cloning, sequencing, and/or polymerase chain reaction mapping to study 15 rearrangements occurring in the MTS1 locus. We found that these breakpoints occur in two clusters (MTS1(bcr alpha) and MTS1(bcr beta)). The three rearrangements occurring in MTS1(bcr alpha) correspond to a recurrent recombination juxtaposing 5' MTS2 exon 1 and 5' MTS1 exon 1 alpha sequences, Breakpoints for 10 of 12 rearrangements within MTS1(bcr beta) are located at a polymorphic (CA) repeat, suggesting that this sequence might play a role in the clustering. For both MTS1(bcr alpha) and MTS1(bcr beta), sequence analyses and PGR mapping experiments show that the tightly clustered breakpoints are located in the vicinity of heptamers whose sequence is similar to those involved in the V(D)J recombination. Moreover, short deletions, GC-rich random nucleotide additions, and clone-specific junctional sequences are present in all cases, further suggesting that the rearrangements are due to illegitimate tr(D)J recombinase activity, These data are the first demonstration that a tumor suppressor gene can be inactivated by the V(D)J recombinational mechanism. Moreover, they reinforce the view that this process, normally required for T-cell differentiation, plays a crucial role in the pathogenesis of T-ALL. (C) 1997 by The American Society of Hematology.