IntroductionB-cell chronic lymphocytic leukemia (B-CLL) represents the most common leukemia in the Western countries with an estimated incidence of 1 per 100 000 per year. The disease is characterized by the monoclonal expansion of B lymphocytes expressing the CD5 marker and exhibiting a long life span, possibly because of a perturbed apoptotic program. 1 Current knowledge of the molecular pathogenesis of B-CLL is limited because no specific genetic alteration has yet been associated with this disease. In particular, B-CLL is not associated with reciprocal balanced chromosomal translocations. 2 Accordingly, none of the proto-oncogenes involved in chromosomal translocations in other mature B cell malignancies, including cyclin D1, 4 Although in a fraction of B-CLL cases, inactivation of the tumor suppressor gene p53 (on chromosome 17p13) and deletions or mutations of the ATM gene (on chromosome 11q22-23) have been reported, 5-9 such lesions were observed in late stages of the disease and may not represent primary tumorigenic events.Chromosome 13q14 deletions (approximately 50% of the patients) 2,10,11 are the commonest chromosomal alterations associated with B-CLL, followed by structural aberrations of chromosome 11q (19% of the cases) and trisomy of chromosome 12 (15%). 2 Moreover, chromosome 13 deletions can be the only cytogenetically detectable abnormality, suggesting an early role in B-CLL pathogenesis. Together, these findings point to the presence in this region of a tumor suppressor gene whose loss or inactivation may be crucial for the leukemogenesis.Deletions of chromosome 13q14 have also been reported in a variety of human tumors, including various other types of lymphoid tumors 12-17 and myeloid leukemias, 18 as well as prostate, 19,20 head and neck, 21 and non-small-cell lung cancers. 22 Although the deleted region of chromosome 13q14 has not yet been defined precisely in most of these neoplasms, these observations suggest that a common tumor suppressor gene may reside on this chromosomal segment.To identify the B-CLL-associated tumor suppressor gene, we previously constructed a high-density contiguous cosmid-based physical map encompassing the deleted interval. 10 This map allowed us to demonstrate that somatic loss at 13q14 occurs in 54% of the patients 10 (and unpublished results) and that the loss is monoallelic in 81% of such cases and biallelic in the remaining 19%. A minimal deleted region (MDR) in B-CLL, spanning less than 300 kilobase (kb) and representing the site of the B-CLLassociated putative tumor suppressor gene, was assigned on our For personal use only. on April 29, 2019. by guest www.bloodjournal.org From physical map in the interval between markers 173a12-82 and 138G4/1.3R. 10 This interval has also been confirmed by other studies. 13 In fact, the MDR exhibits a partial overlap with the regions of deletion as assigned in additional reports, [23][24][25][26] and it includes a locus of 10 kb that was previously defined as a minimal consensus for 13q14 deletion in B-CLL, based on the ...
