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P53 Mutations in Human Lymphoid Malignancies

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P53 Mutations in Human Lymphoid Malignancies Proc. Natl. Acad. Sci. USA Vol. 88, pp. 5413-5417, June 1991 Medical Sciences p53 mutations in human lymphoid malignancies: Association with Burkitt lymphoma and chronic lymphocytic leukemia (tumor suppressor genes) GIANLUCA GAIDANO*, PAOLA BALLERINI*, JERRY Z. GONG*, GIORGIO INGHIRAMI*, ANTONINO NERI*t, ELIZABETH W. NEWCOMB*, IAN T. MAGRATH§, DANIEL M. KNOWLES*, AND RICCARDO DALLA-FAVERA* *Department of Pathology and Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032; tDepartment of Pathology and Cancer Center, New York University School of Medicine, New York, NY 10032; tCentro Malattie del Sangue "G. Marcora," Ospedale Maggiore, 20122 Milan, Italy; and §Pediatric Branch, National Cancer Institute, Bethesda, MD 20892 Communicated by Michael Potter, February 25, 1991 (receivedfor review December 13, 1990) ABSTRACT We have investigated the frequency of p53 alteration may contribute to the deregulated growth charac- mutations in B- and T-cell human lymphoid malancies, teristics ofcancer cells. First, several types ofhuman tumors including acute lymphoblastic leukemia, the major subtypes of display the monoallelic loss of variable portions of the short non-Hodgkin lymphoma, and chronic lymphocytic leukemia. arm of chromosome 17 (5). In the case of colon cancer, it has p53 exons 5-9 were studied by using genomic DNA from 197 been shown that the region 17p13.1, the site of the p53 locus primary tumors and 27 cell lines by single-strand conformation (8), is consistently lost (4). Second, consistent with Knud- polymorphism analysis and by direct sequencing of PCR- son's model of tumor suppressor genes (9), it was found that amplified fragments. Mutations were found associated with (i) the 17p13.1 loss was consistently associated with mutations Burkitt lymphoma (9/27 biopsies; 17/27 cell lines) and its of the residual p53 allele, which are thought to inactivate the leukemic counterpart L3-type B-cell acute lymphoblastic leu- remaining p53 function (4-6). Finally, functional evidence for kemia (5/9), both of which also carry activated c-myc onco- the tumor suppressor role of p53 was achieved by showing genes, and (ii) B-cell chronic lymphocytic leukemia (6/40) and, that normal p53 can inhibit the transformation of rodent cells in particular, its stage of progression known as Richter's and can revert the malignant human transformation (3/7). Mutations were not found at any signif- phenotype of carcinoma icant frequency in other types of non-Hodgkin lymphoma or cells in vitro (10-12). However, p53 may differ in some acute lymphoblastic leukemia. In many cases, only the mutated respects from the prototype of tumor suppressor genes, in allele was detectable, implying loss of the normal allele. These that at least some p53 mutant alleles can behave as dominant results suggest that (i) signicant differences in the frequency oncogenes by transforming target cells in vitro and causing of p53 mutations are present among subtypes of neoplasms tumorigenesis in transgenic mice even in the presence of the derived from the same tissue; (ii) p53 may play a role in tumor normal allele (13, 14). Regardless of the exact mechanism progression in B-cell chronic lymphocytic leukemia; (ii) the involved, p53 mutations and allelic losses can now be con- presence of both p53 loss/inactivation and c-myc oncogene sidered as a relatively frequent pathogenetic feature of sev- activation may be important in the pathogenesis of Burkitt eral types of human malignancies, including those of the lymphoma and its leukemic form L3-type B-cell acute lympho- colon, breast, lung, brain, and soft tissues (refs. 4-6; for blastic leukemia. review, see ref. 15). Several lines ofindirect evidence suggest that alterations of Neoplasia involving the lymphoid system is characterized by the p53 gene might be relevant to the development of lym- marked biological and clinical heterogeneity including malig- phoid neoplasia in humans, including the development of nancies as distinct as acute lymphoblastic leukemia (ALL), lymphomas in transgenic mice carrying mutant p53 alleles non-Hodgkin lymphoma (NHL), chronic lymphocytic leuke- (14), the presence of high levels of p53 expression, typical of mia (CLL), and multiple myeloma. The pathogenesis ofthese tumors harboring p53 mutations, in lymphoproliferative dis- malignancies is also heterogeneous, since distinct molecular orders (16), and the presence of p53 mutations in a few lesions have been found associated with specific subtypes of T-ALL cell lines tested (17). These results have prompted our lymphoid tumors (for review, see ref. 1). These lesions involve comprehensive analysis of the frequency of p53 mutations in "dominantly acting" oncogenes activated either by chromo- a large panel of human lymphoid malignancies, including the somal translocations, affecting c-myc in high-grade NHL and most common types of B- and T-cell tumors. The results affecting bcl-2 in low- and intermediate-grade NHL, or by suggest that p53 mutations are associated with Burkitt lym- point mutations, affecting N-ras in ALL and multiple myeloma phoma (BL), its leukemic counterpart L3-type B-ALL, and (1). However, recent evidence has implied a role for "tumor the late stages of B-CLL. suppressor genes" in tumorigenesis (reviewed in ref. 2), the disruption or loss of which is thought to relieve the cell from negative regulatory signals. While various studies (3-6) have MATERIALS AND METHODS shown that tumor suppressor genes-namely, Rb and p53- Pathologic Samples. Peripheral blood, bone marrow, or are the site of frequent lesions in multiple types of human lymph node samples from 197 patients were collected during tumors, their involvement in human lymphoid malignancies standard diagnostic procedures. For most cases, the fraction has not been comprehensively investigated. of malignant cells in the pathologic specimen was at least The p53 gene (7) encodes a 53-kDa nuclear phosphoprotein 60%, and for all cases it was at least 30%, as determined by that may be involved in the negative regulation ofcell growth. cytofluorometric analysis of cell-surface markers, antigen- Several lines of evidence support the notion that its loss or receptor gene rearrangement analysis, or both (18). DNA was The publication costs of this article were defrayed in part by page charge Abbreviations: ALL, acute lymphoblastic leukemia; NHL, non- payment. This article must therefore be hereby marked "advertisement" Hodgkin lymphoma; CLL, chronic lymphocytic leukemia; BL, Bur- in accordance with 18 U.S.C. §1734 solely to indicate this fact. kitt lymphoma; SSCP, single strand conformation polymorphism. 5413 Downloaded by guest on September 25, 2021 5414 Medical Sciences: Gaidano et al. Proc. Natl. Acad. Sci. USA 88 (1991) purified by digestion with proteinase K, extraction with Table 1. Frequency of p53 mutations in lymphoid malignancies phenol/chloroform, and precipitation by ethanol (19). Diagnosis Positive/tested Cell Lines. The following BL cell lines were used in the present study: CW678, MC116, KK125, JD38, As283A, B-cell tumors EW36, Ramos, ST486, PA682, PP984, CA46, NAB9B, EB3, ALL Daudi, Namalwa, Ag876, P3HR1, Mwika, BL2, BL37, BL47, Precursor B 2/25 BL104, BL84, BL99, BL49, BL60, and BL113 (20, 21). For B-ALL (L3) 5/9 four BL cases (GS 111, BL37, BL60, and BL113), DNA from NHL nontumor cells from the same patients was obtained from Small lymphocytic 0/9 three lymphoblastoid cell lines (IARC176A, IARC277, and Follicular* 0/20 IARC632, normal counterparts of BL37, BL60, and BL113, Diffuset 0/14 respectively) and a T-cell clone (normal counterpart of GS Burkitt 111). Biopsiest 9/27 Oligonucleotide Primers. All of the oligonucleotides used Cell lines§ 17/27 for PCR amplification in this study were synthesized by the B-CLL 6/40 solid-phase triester method (22). Names and sequences ofp53 Richter's transformation 3/7 primers derived from published sequences (23) are as follows: HCL 1/8 P5-5, 5'-TTCCTCTTCCTGCAGTACTC-3' (nucleotides PLL 0/2 911-930); P6-3, 5'-AGTTGCAAACCAGACCTCAG-3' (nu- T-cell tumors cleotides 1249-1268); P7-5, 5'-GTGTTGTCTCCTAGGT- T-ALL 0/7 TGGC-3' (nucleotides 1269-1288); P8-5, 5'-TATCCTGAG- T-CLL 0/9 TAGTGGTAATC-3' (nucleotides 1411-1430); P9-3, 5'- CTCL 0/8 AAGACTTAGTACCTGAAGGGT-3' (nucleotides 1654- PTCL 1/12 1674). In addition, the following primers were used: P5-3, HCL, hairy cell leukemia; PLL, prolymphocytic leukemia; CTCL, 5'-ACCCTGGGCAACCAGCCCTGT-3', derived from in- cutaneous T-cell lymphoma; PTCL, peripheral T-cell lymphoma. tron 5 sequence (spanning nucleotides 26-46 3' to the exon *Follicular small cleaved (13 cases) and follicular mixed (7 cases). 5/intron 5 boundary); P6-5, 5'-ACAGGGCTGGTTGC- tDiffuse mixed (5 cases) and diffuse large cell (9 cases). CCAGGGT-3', derived from intron 5 sequence (spanning tSporadic Burkitt lymphoma (13 cases) and endemic Burkitt lym- 26-46 to exon 5 phoma (14 cases). nucleotides 3' the 5/intron boundary); P7-3, §Sporadic Burkitt lymphoma (19 cell lines) and endemic Burkitt 5'-GTCAGAGGCAAGCAGAGGCT-3', derived from intron lymphoma (8 cell lines). 7 sequence (G.G., unpublished observation; spanning nucle- otides 46-65 3' to exon 7/intron 7 boundary); P8-3, 5'- equivocal diagnosis and a high percentage of malignant cells. AAGTGAATCTGAGGCATAAC-3', derived from intron 8 In addition, 27 BL cell lines and 4 germ-line control tissues, sequence (spanning nucleotides 45-64 3' to exon 8/intron 8 obtained from the corresponding tumor patients, were in- boundary); P9-5, 5'-GCAGTTATGCCTCAGATTCAC-3', cluded in this study. derived from intron 8 sequence (spanning nucleotides 42-62 A two-step experimental approach was devised. By SSCP 3' to exon 8/intron 8 boundary). analysis (24), all samples were analyzed for mutations within Single-Strand Conformation Polymorphism (SSCP) Analy- exons 5-9 of the p53 gene, which are the regions most sis. SSCP analysis was accomplished according to an adapted version of a previously reported method (24). Briefly, PCRs frequently affected by mutations in other types of human were performed with 100 ng of genomic DNA, 10 pmol of tumors (4-6).
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