BCL6 and Cytogenetics

Chromosomal translocations produce their effects in malignant disease essentially by one of two mechanisms. First, a fusion gene can be produced that commonly has a modular structure, for example, a DNA binding domain from one gene is joined to an effector domain from a different gene or, second, translocation can cause overexpression of a gene whose effects are to enhance cell growth or prevent apoptosis. It is surprising that fusion genes are found predominantly in myeloid malignancies, whereas translocations causing overexpression of an unaltered gene occur in lymphoproliferative conditions.

BCL-6 rearrangement in DLCL conforms to this paradigm. The major breakpoint region is within the 5' noncoding region of the BCL-6 gene in approximately half of all cases that have chromosomal translocations involving the BCL-6 locus at 3q27. Some of the remaining cases, between 30% and 50%, have breakpoints that are 245 to 285 kb upstream of BCL-6 (34). In both of these situations, it is presumed that BCL-6 comes under the transcriptional control of elements, which drive the gene constitutively (34,35).

In 52-58% of cases of DLCL that have translocations involving 3q27, an immunoglobulin gene locus is brought close to BCL-6 (36,37). One of these studies (36) further demonstrated that 74% (22/30) of these cases use the immunoglobulin heavy chain locus, 3% (1/30) the kappa light chain locus,

Table 1

Partner Loci Involved In BCL-6 Translocations

Table 1

Partner Loci Involved In BCL-6 Translocations

Translocation

Nonimmunoglobulin Locus

Gene class

Reference

t(3;16)(q27;p11)

Interleukin 21

Cytokine receptor

38

receptor

t(3;6)(q27;p21)

SRP20

Regulation of pre-

39

mRNA splicing

t(3;13)(q27;q14)

L-plastin

Actin binding protein

40

t(3;7)(q27;p12

Ikaros

Regulator of lymphocyte

41,42

differentiation

t(3;4)(q27;p13)

RhoH/TTF

Rho GTP binding protein

43

t(3;11)(q27; q23)

BOB1/OBF1

B lymphocyte transcription

44

factor

H4

Histone

36

HSP89alpha

Heat shock protein

36,76

HSP90beta

Heat shock protein

36

PIM-1

Lymphocyte growth factor

36 43

and proto-oncogene

MHC class II

Transcription factor

42

transactivator

Eukaryotic initiation

Transcription factor

42

factor 4AII

Transferrin receptor

Surface receptor

42

Where no chromosomal translocation is given, the partner locus has been discovered by longrange PCR.

Where no chromosomal translocation is given, the partner locus has been discovered by longrange PCR.

and 23% (7/30) the lambda light chain locus. Analysis of the heavy chain locus demonstrated that breakpoints occur within the switch region (35), similar to the translocations between the same immunoglobulin locus and c-MYC in sporadic cases of Burkitt's lymphoma, and suggesting that these chromosomal events occur at a late stage in B-cell development rather than during variable-diversity-joining, that is, V-D-J, rearrangement in the bone marrow. In approx 40% of DLCL cases, translocations do not involve the immunoglobulin locus. These appear to have a worse prognosis than those with an altered immunoglobulin locus (37). The nonimmunoglobulin loci that have been identified in translocations are detailed in Table 1.

As has been mentioned previously, diffuse lymphoma is a heterogeneous disease both histologically and molecularly (32,33), and one outcome of this is that chromosomal translocations involving other genes are also found. One study (46) using Southern analysis found 15.3% of cases to have a BCL-1 translocation, 5.8% BCL-2 translocation, and 10.2% a c-MYC translocation. A combined cytogenetic and gene expression study (47) demonstrated the t(14;18)(q32;q21) translocation, that is, disrupting the BCL-2 locus, in 20% of cases of diffuse lymphoma and all of these had a germinal center B-cell gene expression signature (31) of which BCL-6 expression is a feature.

In a minority of cases translocations involving 3q27 are associated with other cytogenetic abnormalities. For example, one series (48) found 3/22 cases to also bear a disrupted BCL2 locus t(14;18) and 2/22 to bear a disrupted c-MYC locus t(8;14). Cases in which all three common translocations occur together have been reported (49).

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