Chromosome

Deletion in the long arm of chromosome 13 at band 13q14 is the most frequently observed clonal abnormality, detected by interphase FISH in more than half (55%) of CLL cases (2-5). Deletions at 13q have been associated with other lymphoid malignancies and with poor prognosis in these diseases, such as mantle cell lymphoma (50%) (6,7) and multiple myeloma (16-40%) (8-10), as well as malignancies of other hematologic lineages (11).

There is intense ongoing research to identify a putative tumor suppressor gene or genes involved in 13q deletion; several groups have identified the breakpoint at 13q14 (3,12-15). The retinoblastoma (RB-1) gene (at 13q14) encodes a nuclear phosphoprotein involved in cell cycle control and transcription regulation (16) and was once considered a candidate tumor suppressor gene affected in CLL. However, RB-1 is an unlikely candidate since homozygous mutations as well as loss of heterozygosity through mutation are very rare in CLL, and abnormal concentrations of RB-1 protein are not reported in CLL (14). Furthermore, analyses have indicated that the deleted region is approx 1.6 cM telomeric to the RB-1 and centromeric to the D13S25 marker (17-19).

Table 1

Influence of Chromosome Abnormalities in CLL

Chromosome abnormality Frequency (%)

13q deletion 10-55

Trisomy 12 20-30

11q deletion 5-18

17p deletion 10-15

6q deletion 6-8

Significance

Most common

Favorable prognosis

Typical cell morphology

Associated with mutated IgVH genes

Atypical morphology

Acquired with clonal evolution

Unfavorable prognosis

Associated with mutated ATM gene

Atypical (prolymphocytic) morphology

Unfavorable prognosis in age < 55 yr

Associated with mutated or deleted P53 gene

Atypical (prolymphocytic) morphology

Associated with unmutated IgVH genes

Resistant to chemotherapy

Unfavorable prognosis

Atypical cell morphology

May involve TNF1 gene

The putative tumor suppressor gene located in this region (referred to as DBM, for disrupted in ¿-cell malignancies) remains to be confirmed. Several candidate genes have been suggested, including LEU1, LEU2, LEU5, CLLD6, CLLD7, CLLD8, ALT1, BCMS, and FAM10A4 (Fig. 1) (20-26). More recently, the supposed minimal deleted region, narrowed down to a 650-790 kb region between markers D13S319 and D13S25, has been completely sequenced (27).

The candidate tumor suppressor genes that map to the 13q14 region, centromeric to D13S272, include LEU1 and LEU2 (20). The LEU1 gene encodes a 1.1-kb mRNA transcript, and LEU2 encodes two mRNA transcripts of 1.8 and 1.4 kb. CLL cells do not appear to have mutations in both alleles of these genes, making it unlikely that they are tumor suppressor genes in CLL (28). ALT1 and BCMS are splice variants encompassing the LEU1 or LEU2 gene and may prove to be important tumor suppressor genes (24,25). Another candidate tumor suppressor gene is LEU5 (22). This gene encodes a zinc-finger domain of the RING type and shares homology with genes involved in tumorigenesis, including the RET finger protein and BRCA1. The most recently reported gene, FAM10A4, maps to the minimally deleted region and may be an important tumor suppressor gene (26). The search continues for one or more tumor suppressor genes at this location with functional confirmation.

Patients with 13q deletion have a similar survival as individuals with a diploid karyotype and significantly better than patients with 11q or 17p deletions (1,2,29,30). Consistent with the favorable prognosis is the association of 13q deletion with other characteristics associated with favorable prognosis including low CD38 expression and somatic hypermutation of the Ig variable region (IgVH) gene (31-33).

Fig. 1. Chromosome 13q14. Physical map of the critical region of chromosome 13q14 with relative size and position of proposed CLL-associated genes mapping to this region.

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