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A common 93-kb duplicated DNA sequence at 1q21.2 in acute lymphoblastic leukemia and Burkitt lymphoma

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Abstract

In three patients with acute lymphoblastic leukemia (ALL) and in another with Burkitt lymphoma (BL), conventional cytogenetics and fluorescence in situ hybridization (FISH), applied singly or in combination, showed 1q duplication in two cases of ALL with hyperdiploid karyotypes, 1q duplication resulting from an unbalanced translocation in a third case of ALL, and inv dup(1)(q) in a patient with BL. Centromeric or telomeric breakpoints and extension of the 1q duplicons varied in each case. FISH defined a minimal, common duplicated region of 93kb at band 1q21.2 corresponding to clone RP11-212K13. In this region three putative oncogenes or tumor suppressor genes have been mapped: SF3B4 (splicing factor 3b, subunit 4), OTUD7B (OTU domain containing 7B), and MTMR11 (myotubularin related protein 11). For the first time, a minimal common 1q21.2 duplicated sequence has been identified in lymphoid malignancies in a region where putative oncogenes or suppressor genes have been mapped. This finding elucidates the genomic background of ALL and BL with 1q duplication and provides the basis for molecular studies investigating which genes are involved in leukemogenesis or disease progression in these cases.

Introduction

Chromosome 1 long arm duplications, or dup(1q), and trisomy 1q are recurrent changes in chronic myeloproliferative disorders, multiple myeloma (MM), acute lymphoblastic leukemia (ALL), and Burkitt lymphoma/leukemia (BL).

In chronic myeloproliferative disorders, both a 1q23∼q32 duplication and an unbalanced 1q translocation with various chromosomes, producing a gain of the entire 1q arm, have been observed [1]. In up to 40% of patients with MM, 1q12∼q32 duplications, whole-arm translocations, or jumping translocations are associated with complex karyotypes, aggressive disease, and poor prognosis [2]. In BL, dup(1q) is the most frequent secondary change associated with t(8;14)(q24;q32); it appears to be linked to disease progression rather than pathogenesis [3], [4]. Whether dup(1q) and trisomy 1q in lymphoid and myeloid malignancies underlie the same molecular lesions remains to be established.

We characterized dup(1q) in lymphoid malignancies and identified a common 1q21.2 duplicated region in three cases of ALL and one case of BL. Our findings provide the basis for designing molecular studies to investigate any putative oncogenes or tumor suppressor genes that could underlie 1q duplication in ALL and BL.

Section snippets

Patients

We studied three ALL (patients 1–3) and one BL (patient 4) at diagnosis (Table 1). Conventional cytogenetic and fluorescence in situ hybridization (FISH) analyses were performed on bone marrow cells (patients 1–3) and pleural and ascitic effusion (patient 4).

Cytogenetics

Karyotypes were obtained on G-banded metaphases after 24- and 48-hour cultures and were described according to ISCN 2005 [5].

FISH

Metaphase FISH was performed in dual-color experiments, as previously described, with 34 DNA clones for the 1q arm

Patients

Two of the patients were male (1 ALL; 1 BL) and two were female (2 ALL). Two ALL patients and the one BL patient were children (5, 9, and 11 years old) and one ALL patient was a 46-year-old adult. Clinical and hematological features and cytogenetic findings are summarized in Table 1.

Cytogenetics

In patients 1 and 2, dup(1q) was present in hyperdiploid karyotypes. Patient 3 had three leukemic clones. A reciprocal t(1;18)(q21;q12) was common to all. It was isolated in the main clone and associated with

Discussion

The genomic mechanisms and molecular lesions underlying dup(1q) in lymphoid malignancies remain to be established. To date, FISH studies have mapped dup(1q) centromeric breakpoints in the centric or pericentric region of chromosome 1 within, or in close proximity to, the heterochromatic sequences [10]. The present study identified a minimal common duplicated DNA euchromatic sequence in four cases of ALL/BL.

Although 1q duplicons in ALL and BL have various sizes with different proximal and distal

Acknowledgments

AIRC (Associazione Italiana Ricerca sul Cancro), CNR-MIUR (Consiglio Nazionale delle Ricerche-Ministero per l'Istruzione, l'Università e la Ricerca Scientifica); Fondazione Cassa di Risparmio, Perugia, Italy; FIRB, Italy; and Associazione “Sergio Luciani,” Fabriano, Italy. B.C. is supported by a grant from FIRC (Fondazione Italiana Ricerca sul Cancro). BAC clones were kindly provided by Dr. Mariano Rocchi (DAPEG Sez di Genetica, University of Bari, Italy); Telomeric DNA clones were kindly

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