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Deletions of PURA, at 5Q31, and PURB, at 7P13, in Myelodysplastic Syndrome and Progression to Acute Myelogenous Leukemia K Lezon-Geyda1,2, V Najfeld2 and EM Johnson1

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Deletions of PURA, at 5Q31, and PURB, at 7P13, in Myelodysplastic Syndrome and Progression to Acute Myelogenous Leukemia K Lezon-Geyda1,2, V Najfeld2 and EM Johnson1 Leukemia (2001) 15, 954–962 2001 Nature Publishing Group All rights reserved 0887-6924/01 $15.00 www.nature.com/leu Deletions of PURA, at 5q31, and PURB, at 7p13, in myelodysplastic syndrome and progression to acute myelogenous leukemia K Lezon-Geyda1,2, V Najfeld2 and EM Johnson1 1Departments of Pathology, Biochemistry and Molecular Biology, the Derald H Ruttenberg Cancer Center; and 2Tumor Cytogenetics Laboratory, Polly Annenberg Levee Hematology Center, Mount Sinai School of Medicine, New York, NY, USA Deletions or monosomy of chromosomes 5 and 7 are frequently gle gene product, the levels of which are critical, may be con- observed in myelodysplastic syndromes (MDS) and acute myel- ferred by haploinsufficiency.16 Similarly, no tumor suppressor ogenous leukemia (AML). In this study two genes, PURA and PURB, encoding functionally cooperative proteins in the Pur genes have yet been identified at deleted loci on chromosome family, are localized to chromosome bands 5q31.1 and 7p13, 7. The possibility has been noted that tumor suppressor genes respectively. One or both of these loci are shown to be hemiz- are present at more than one site on the long arms of chromo- ygously deleted in 60 MDS or AML patients using fluorescence some 7,17 as deletions of 7q are more frequently seen in MDS in situ hybridization (FISH). High-resolution mapping of PURA patients than deletions in 7p.1 On the other hand, deletions localizes it approximately 1.1 Mb telomeric to the EGR-1 gene. of 7p are seen in a significant number of cases,1,18 and thus Frequency of PURA deletion and segregation with EGR-1 indi- cate that PURA is within the most commonly deleted segment it is conceivable that the high prevalence of monosomy 7 in myeloid disorders characterized by del(5)(q31). No mutations reflects the critical nature of multiple genes on both the short have been detected within the coding sequence of PURA. Con- and long arms of chromosome 7. current deletions of PURA and PURB occur in MDS at a rate Pur is a family of sequence-specific single-stranded DNA- nearly 1.5-fold higher than statistically expected and in AML at binding proteins that have an affinity for a purine-rich . a rate 5-fold higher. This novel simultaneous deletion of two element.19,20 Human Purα is encoded by the PURA gene, closely related gene family members may thus have conse- 21 quences related to progression to AML. Purα, an Rb-binding localized to chromosome 5, band region 5q31. Expression protein, has been implicated in cell cycle control and differen- of the PURA gene has been observed in all tissues analyzed, tiation, and Purα and Purβ are reported to function as heterodi- and the protein is highly conserved across several species.22–24 mers. Alterations in these genes could affect a delicate balance Purα has been implicated in control of DNA replication,22,25,26 critical in myeloid development. Leukemia (2001) 15, 954–962. and it has been reported to be a transcriptional activator of Keywords: Pur; MDS; AML; chromosome 5; chromosome 7; haplo- both viral27 and mammalian23,28,29 promoters. insufficiency A second family member, Purβ, is more than 70% homolo- gous to Purα,19 and Purβ reportedly functions in a complex with Purα.20 Binding of the Purα homodimer to the myelin Introduction basic protein gene promoter has been reported to activate transcription.27 In contrast, binding of the Purα/Purβ hetero- Monosomy of chromosomes 5 and 7 or deletion of their long dimeric complex to the mouse vascular smooth muscle α- − − arms [ 5/del(5q); 7/del(7q)] are frequently observed chromo- actin gene enhancer results in transcriptional repression.30 The somal abnormalities in myeloproliferative disorders, and kinetics of dimerization of these two proteins is very likely specifically in de novo MDS, in which each is observed in sensitive to any change in the intracellular levels of each. We 1–3 about 30% of the cases. Therapy-related MDS (t-MDS) and report here that the human gene that encodes the Purβ protein therapy-related AML (t-AML) are associated with a higher fre- is mapped to the short arms of chromosome 7, band region quency of karyotypic abnormalities, often including 7p13. − − 5/del(5q) and 7/del(7q). Nearly 71% of patients with t- For the present study we have analyzed samples from 60 MDS/t-AML have abnormalities of chromosomes 5 and/or 7, patients with myeloid disorders. A high percentage of these and approximately 22% have abnormalities of both 5 and 7 patients have hemizygous deletions of either the PURA or 4,5 simultaneously. PURB loci, and a substantial percentage have deletions of In MDS and AML the deletions of the long arms of chromo- both loci. In the majority of patients with MDS the overall some 5 are frequently interstitial and the breakpoints are vari- occurrence of simultaneous deletion of PURA and PURB loci 6,7 able. The most commonly deleted segment of 5q in MDS, are higher than predicted on the basis of occurrence of hemiz- within band region 5q31, is a subject of considerable investi- ygous deletion of either one individually. These data com- 5,8–11 gation. Many genes involved in myeloid cell growth and bined with evidence that the intracellular level of the Purα differentiation have been mapped to band region 5q31, protein is critical for proliferation and differentiation render 12 5 13 including IRF1, IL-9, EGR-1, CDC25C, CD14, and possible a haploinsufficiency phenomenon in which a com- 14 Smad5. It has frequently been speculated that the deletion plex of two cooperating proteins is affected. of this chromosomal region leads to inactivation of one or more tumor suppressor genes. To date, however, none of the genes analyzed has been demonstrated to be a tumor sup- Materials and methods pressor of myeloid cell lineage. It thus remains possible that either deletion of genetic material leads to the imbalance of 15 Patients, samples, and conventional cytogenetic several important gene products, or loss of function of a sin- findings Correspondence: K Lezon-Geyda, Box 1079, Tumor Cytogenetics, Fixed cytogenetic bone marrow samples from 90 individuals Mount Sinai School of Medicine, New York, NY 10029, USA; Fax: were selected and obtained following routine cytogenetic (212) 996–1029 analysis in the Tumor Cytogenetics Laboratory at The Mount Loss of PURA and PURB in myeloid disorders K Lezon-Geyda et al 955 Sinai Medical Center. Karyotypes were designated according clones, 153O15 and 507K3, were obtained from Research to the International System for Human Cytogenetic Nomencla- Genetics (Huntsville, AL, USA) based on a screen of CITB ture.31 Three groups of 30 individuals were identified for this Human BAC Resources for PURA by polymerase chain reac- study: (1) patients diagnosed with MDS or AML and identified tion (PCR). The PCR screen was done using primers specific to have normal karyotypes; (2) patients diagnosed with MDS for a 188 bp sequence of the human PURA gene. In addition or AML and identified to have abnormal karyotypes including two STS-BAC pairs (clones identified to contain a specific STS abnormalities of chromosomes 5 and/or 7; and (3) healthy marker) D5S658 and D5S487, mapped to 5q, were obtained bone marrow transplantation donors. In order to investigate from the laboratory of Dr J Korenberg (Cedars- Sinai Medical possible microdeletions of loci in band region 5q31, 30 of the Center, UCLA, Los Angeles, CA, USA). BAC clone GS025I23, 60 patients selected for this study possessed a normal kary- which contains the 7p genomic marker sWSS1147,34 also otype. Of the 30, 22 had MDS and eight had AML. Of the 30 called STS D7S478, and which we reveal to contain PURB, with abnormal karyotypes (Tables 1 and 2), 24 had MDS and was obtained from Genome Systems (St Louis, MO, USA). The six had AML. Nine patients (No. 17 and Nos 22–29) had con- BAC DNA was prepared as described by Hubert et al,35 pur- comitant abnormalities of chromosomes 5 and 7 as part of ified on Qiagen columns (Qiagen, Valencia, CA, USA), treated their complex karyotypes. Only three of the 60 patients had with RNase A (Roche Molecular Biochemicals, Indianapolis, secondary disease due to therapy for other malignancies IN, USA), and extracted with phenol/chloroform prior to (Nos 24–26). The primary malignancy diagnosed for patient labeling. No. 24 was lymphoma and for patients Nos 25 and 26 it was breast cancer. Thirty additional samples from healthy bone marrow donors with normal cytogenetics were employed as controls for this study. DNA probes for fluorescence in situ hybridization Bacterial artificial chromosome sources and preparation Labeling of BAC DNA probes with biotin or digoxigenin (DIG) was performed using either Biotin or DIG Nick Translation Bacterial artificial chromosome (BAC) clones isolated from Mix (Roche Molecular Biochemicals). The EGR-1 LSI 5q31 libraries constructed at Caltech32,33 were obtained from three probe in Spectrum Orange and Whole Chromosome Paint 5 sources for this study. (Note that ‘BAC’ denotes a DNA clone (WCP 5) probe in Spectrum Green were obtained from Vysis and ‘bac’ denotes a polymorphic genomic marker.) Two BAC (Downers Grove, IL, USA). Table 1 Clinical and cytogenetic data of cases analyzed for loss of PURA Patient S/A Diagnosis Karyotype 1 F/75 AML 46,XX,del(5)(q14q32) [30] 2 F/66 MDS 46,XX,del(5)(q12q31) [13]/46,XX [8] 3 M/89 MDS 46,XY,del(5)(q13q32) [2]/46,idem,del(13)(q12q21) [9]/46,XY [12] 4 M/71 MDS 46,XY,del(5)(q14q32),del(20)(q12) [22]/46,XY [6] 5 M/69 AML 42,XY,dic(1;2)(q23;q34),t(3;12)(p12;p13),del(5)(q12q34),del(13) (q13q31),del(14)(q12q24)add(17)(p11),−17,−18,−20,add(22)(q13)
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