Russell Lisa J, Capasso Melania, Vater Inga, Akasaka Takashi, Bernard Olivier A, Calasanz Maria Jose, Chandrasekaran Thiruppavaii, Chapiro Elise, Gesk Stephan, Griffiths Mike, Guttery David S, Haferlach Claudia, Harder Lana, Heidenreich Olaf, Irving Julie, Kearney Lyndal, Nguyen-Khac Florence, Machado Lee, Minto Lynne, Majid Aneela, Moorman Anthony V, Morrison Heather, Rand Vikki, Strefford Jonathan C, Schwab Claire, Tönnies Holger, Dyer Martin J S, Siebert Reiner, Harrison Christine J
Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle, United Kingdom.
Blood. 2009 Sep 24;114(13):2688-98. doi: 10.1182/blood-2009-03-208397. Epub 2009 Jul 29.
We report 2 novel, cryptic chromosomal abnormalities in precursor B-cell acute lymphoblastic leukemia (BCP-ALL): a translocation, either t(X;14)(p22;q32) or t(Y;14)(p11;q32), in 33 patients and an interstitial deletion, either del(X)(p22.33p22.33) or del(Y)(p11.32p11.32), in 64 patients, involving the pseudoautosomal region (PAR1) of the sex chromosomes. The incidence of these abnormalities was 5% in childhood ALL (0.8% with the translocation, 4.2% with the deletion). Patients with the translocation were older (median age, 16 years), whereas the patients with the deletion were younger (median age, 4 years). The 2 abnormalities result in deregulated expression of the cytokine receptor, cytokine receptor-like factor 2, CRLF2 (also known as thymic stromal-derived lymphopoietin receptor, TSLPR). Overexpression of CRLF2 was associated with activation of the JAK-STAT pathway in cell lines and transduced primary B-cell progenitors, sustaining their proliferation and indicating a causal role of CRLF2 overexpression in lymphoid transformation. In Down syndrome (DS) ALL and 2 non-DS BCP-ALL cell lines, CRLF2 deregulation was associated with mutations of the JAK2 pseudokinase domain, suggesting oncogenic cooperation as well as highlighting a link between non-DS ALL and JAK2 mutations.
我们报告了前体B细胞急性淋巴细胞白血病（BCP-ALL）中的2种新的隐匿性染色体异常：33例患者存在t(X;14)(p22;q32)或t(Y;14)(p11;q32)易位，64例患者存在del(X)(p22.33p22.33)或del(Y)(p11.32p11.32)间质缺失，这些异常涉及性染色体的假常染色体区域（PAR1）。这些异常在儿童ALL中的发生率为5%（易位为0.8%，缺失为4.2%）。易位患者年龄较大（中位年龄16岁），而缺失患者年龄较小（中位年龄4岁）。这2种异常导致细胞因子受体、细胞因子受体样因子2（CRLF2，也称为胸腺基质衍生的淋巴细胞生成素受体，TSLPR）的表达失调。CRLF2的过表达与细胞系和转导的原代B细胞祖细胞中JAK-STAT通路的激活相关，维持它们的增殖，并表明CRLF2过表达在淋巴细胞转化中起因果作用。在唐氏综合征（DS）ALL和2种非DS BCP-ALL细胞系中，CRLF2失调与JAK2假激酶结构域的突变相关，提示致癌协同作用，并突出了非DS ALL与JAK2突变之间的联系。
