Pinyol M, Hernández L, Martínez A, Cobo F, Hernández S, Beà S, López-Guillermo A, Nayach I, Palacín A, Nadal A, Fernández P L, Montserrat E, Cardesa A, Campo E
Department of Hematology, University of Barcelona, Spain.
Am J Pathol. 2000 Jun;156(6):1987-96. doi: 10.1016/S0002-9440(10)65071-7.
INK4a/ARF locus codes for two different proteins, p16(INK4a) and p14(ARF), involved in cell cycle regulation. p14(ARF) is considered an upstream regulator of p53 function. To determine the role of these genes in the pathogenesis of human non-Hodgkin's lymphomas we have analyzed exon 1beta, 1alpha, and 2 of the INK4a/ARF locus and p53 gene aberrations in 97 tumors previously characterized for p16(INK4a) alterations. p53 alterations were detected in four of 51 (8%) indolent lymphomas but in 15 of 46 (33%) aggressive tumors. Inactivation of p14(ARF) was always associated with p16(INK4a) alterations. Exon 1beta was concomitantly deleted with exon 1alpha and 2 in eight tumors. One additional lymphoblastic lymphoma showed deletion of exon 1alpha and 2 but retained exon 1beta. No mutations were detected in exon 1alpha and 1beta in any case. Two of the three mutations detected in exon 2 caused a nonsense mutation in the p16(INK4a) reading frame and a missense mutation in the ARF reading frame involving the nucleolar transport domain of the protein. The third mutation was a missense mutation in the p16(INK4a) reading frame, but it was outside the coding region of p14(ARF). Aggressive lymphomas with p14(ARF) inactivation and p53 wild type showed a significantly lower p53 protein expression than tumors with no alteration in any of these genes. In this series of tumors, inactivation of the INK4a/ARF locus mainly occurred in tumors with a wild-type p53 gene because only two lymphomas showed simultaneous aberrations in these genes. Tumors with concomitant alterations of p16(INK4a) and p14(ARF)/p53 genes seem to exhibit a worse clinical behavior than lymphomas with no alterations or isolated inactivation of any of these genes. These findings indicate that p14(ARF) genetic alterations occur in a subset of aggressive NHLs, but they are always associated with p16(INK4a) aberrations. Concomitant disruption of p16(INK4a) and p14(ARF)/p53 regulatory pathways may have a cooperative effect in the progression of these tumors.
INK4a/ARF基因座编码两种不同的蛋白质，即p16(INK4a)和p14(ARF)，它们参与细胞周期调控。p14(ARF)被认为是p53功能的上游调节因子。为了确定这些基因在人类非霍奇金淋巴瘤发病机制中的作用，我们分析了97例先前已确定p16(INK4a)改变的肿瘤中INK4a/ARF基因座的外显子1β、1α和2以及p53基因的畸变情况。在51例惰性淋巴瘤中有4例（8%）检测到p53改变，但在46例侵袭性肿瘤中有15例（33%）检测到p53改变。p14(ARF)的失活总是与p16(INK4a)的改变相关。在8例肿瘤中外显子1β与外显子1α和2同时缺失。另外1例淋巴母细胞淋巴瘤显示外显子1α和2缺失，但保留了外显子1β。在任何情况下，外显子1α和1β均未检测到突变。在外显子2中检测到的3个突变中有2个在p16(INK4a)阅读框中导致无义突变，在ARF阅读框中导致错义突变，该错义突变涉及该蛋白的核仁运输结构域。第3个突变是p16(INK4a)阅读框中的错义突变，但它位于p14(ARF)的编码区域之外。p14(ARF)失活且p53野生型的侵袭性淋巴瘤与这些基因均无改变的肿瘤相比，p53蛋白表达显著降低。在这一系列肿瘤中，INK4a/ARF基因座的失活主要发生在p53基因野生型的肿瘤中，因为只有2例淋巴瘤显示这些基因同时发生畸变。p16(INK4a)和p14(ARF)/p53基因同时改变的肿瘤似乎比这些基因无改变或仅有孤立失活的淋巴瘤表现出更差的临床行为。这些发现表明，p14(ARF)基因改变发生在一部分侵袭性非霍奇金淋巴瘤中，但它们总是与p16(INK4a)畸变相关。p16(INK4a)和p14(ARF)/p53调节途径的同时破坏可能在这些肿瘤的进展中具有协同作用。
