Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma

Although morphologically and immunophenotypically similar, genetic testing has proven that several different

Figure 32-1. Configuration of the IGH gene on chromosome 14q32. DJ rearrangement occurs initially, followed by VD rearrangement. The rearrangements occur in a random fashion, resulting in a pattern of rearrangements that is unique to each normal B cell. The variable region of the rearranged IGH gene contains one VH segment (plus all the upstream VH segments), one DH segment, one JH (plus all the downstream JH segments), and the CH segments, in that order on the chromosome.

Figure 32-1. Configuration of the IGH gene on chromosome 14q32. DJ rearrangement occurs initially, followed by VD rearrangement. The rearrangements occur in a random fashion, resulting in a pattern of rearrangements that is unique to each normal B cell. The variable region of the rearranged IGH gene contains one VH segment (plus all the upstream VH segments), one DH segment, one JH (plus all the downstream JH segments), and the CH segments, in that order on the chromosome.

Table 32-2.

Nonrandom Chromosomal Abnormalities in B-Cell Lymphomas

Lymphoma

Subtype

Nonrandom Chromosomal Alterations Genes Involved Assay Used for Diagnosis/Prognosis*

CLL/SLL

Del 13q14 Trisomy 12 Del 11q22-23 Del 17p13

Unknown Unknown ATM TP53

FISH FISH FISH,

FISH, karyotyping

LPLt

t(9;14)(p13;q32)

PAX5/IGH

FISH, karyotyping

MZL

t(11;18)(q21;q21) t(1;14)(p22;q32) t(14;18)(q32;q21) Trisomy 3 Trisomy 18

API2/MALT1

BCL10/IGH

IGH/MALT1

?BCL6

Unknown

FISH, PCR FISH, PCR FISH FISH FISH

FL

t(14;18)(q32;q21)

IGH/BCL2

FISH, PCR

MCL

t(11;14)(q13;q32)

Cyclin D1/IGH

FISH for t(11;14)

t(14;18)(q32;q21)

BCL6 IGH/BCL2

FISH, SBA FISH, PCR

BL/BLL

IGLK/MYC

MYC/IGLL

FISH, SBA

*The assays listed are those most commonly used today for clinical testing, but many of these abnormalities also can be detected by other techniques.

fThe involvement of the PAX5/IGH translocation in LPL has been reported by only one laboratory and has not been confirmed subsequently, so it may not be a relevant translocation in this disease. The other molecular abnormalities listed have been confirmed by multiple

sources.

diseases have been included in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), with different chromosomal abnormalities, natural histories, and responses to therapy. Established adverse prognostic biologic factors in CLL/SLL include CD38 antigen expression (detected by flow cytometry), lack of significant IgVH mutation, and the presence of TP53 or ATM gene defects. Many of the relevant chromosomal abnormalities in CLL/SLL are not detected by karyotyping; however, these abnormalities usually are detected by fluorescence in situ hybridization (FISH). Evaluation at diagnosis for these abnormalities is clinically indicated in most cases, as therapeutic decisions are affected by the genetic profile identified. Important specific genetic alterations in CLL/SLL are discussed below.

Somatic Hypermutation of IGH Variable Gene Region

Seen in ~50% of CLL/SLL patients, unmutated IgVH status has been reported to predict poor clinical outcome. However, recent studies have suggested that the poor outcome associated with IgVH mutation levels of <5% may, in fact, be due to overrepresentation of patients with TP53 dysfunction or CD38 expression, or both, in the unmutated IgVH group.5-7 Patients with intact TP53 function and absence of CD38 expression appear to have prolonged survival regardless of the extent of IgVH mutation. As the measurement of IgVH mutation status requires multiple polymerase chain reactions (PCRs) and sequencing of PCR products, this test is currently performed for research purposes only.

Deletions of 13q

As a single abnormality in CLL/SLL, 13q14 deletions convey the most favorable prognosis. CLL/SLL patients with 13q14 abnormalities most often also have IgVH gene hypermutation. Detected by FISH, 13q14 deletions are seen in 40% to 55% of CLL/SLL cases and are thought to affect one or more tumor suppressor genes. Frequent deletions and downregulation of microRNA genes miR15 and miR16 at 13q14 have been described recently in the majority of CLL/SLL cases.8 13q14 deletions are sometimes seen in other BCLs, but the specific gene(s) involved may not be the same.

Trisomy 12

Detected by FISH or routine karyotyping in 16% to 20% of CLL/SLL cases (FISH illustration in Figure 32-2b), trisomy 12 usually is associated with unmutated IgVH genes and also has been associated with atypical CLL. Patients with trisomy 12 have an intermediate prognosis, with a median survival exceeded only by patients with single 13q14 abnormalities.

del 11q22-23-ATM

tri 12

p53m (red) / ATM (green)

CEP12 (green)

b

del 17p13.1-p53

t(11;14)

Deleted Normal

«

p53m (red) / ATM (green)

lgH-14q32 (green) / cyclin D1-11q13 (red)

t(8;14)

t(14;18)

J ■ J/

» •

i

lgH-14q32 (green) / C-MYC-8q24 (red)/ CEP8 (aqua)

lgH-14q32 (green) / BCL2-18q21 (red)

Figure 32-2. Illustration of some typical genetic abnormalities in BCL, detected by interphase FISH. (a) CLL/SLL lymphocyte with an ataxia telangiectasia (ATM) (11q22.3) deletion. The cell shows two red TP53 (17p13.1) signals but only one green ATM signal (RRG).A normal cell would have two red and two green signals (RRGG).(b) A centromeric probe for chromosome 12 demonstrates trisomy 12 (RRR) in this cell from the blood of a CLL/SLL patient. A normal cell would have two red signals (RR). (c) In contrast to the first image, the abnormal cell in this CLL/SLL blood smear shows a deletion of the TP53 gene, but normal ATM signals (RGG). The normal cells show an RRGG signal pattern. (d) A translocation pattern (RGYY) is seen in this cell, using probes that detect both derivative chromosomes resulting from the t(11 ;14)(q 13;q32) BCL1/IGH translocation in a patient with mantle cell lymphoma (MCL). Both derivative chromosomes produce a yellow fusion signal, while the normal alleles produce separate red and green signals.

(e) A complex interphase FISH pattern with the IGH, MYC,and centromeric chromosome 8 probes in cells from a lymph node biopsy in a patient with a Burkitt-like lymphoma (BLL). FISH testing with a probe set for the t(8;14) MYC/IGH translocation and a centromeric probe for chromosome 8 showed an abnormal signal pattern for both IGH and MYC, but no translocation fusion signal. Instead,the cells have four red MYC signals,three green IGH signals,and two aqua centromeric 8 signals (RRRRGGGAA); there are no yellow fusion signals. This patient was subsequently found to have an antecedent follicular lymphoma (FL), with transformation to a BLL. (f) Subsequent FISH analysis of cells from the same lymph node in (e) showed a typical translocation pattern (RGYY) with the probe set for the IGH/BCL2 translocation characteristic of FL.The dual fusion probe set detected both derivative chromosomes from the t(14;18)(q21;q32) IGH/BCL2 translocation. No fusion partner was identified for the MYC rearrangement.

Deletions in 11q22-23

Seen in 14% to 20% of CLL/SLL cases, deletions in 11q22-23 are associated with mutation and inactivation of the ataxia telangiectasia (ATM) gene. The ATM protein kinase is involved in TP53 regulation, and ATM deletions produce TP53 dysfunction in CLL/SLL cells. ATM deletions most often are detected by FISH (illustration in Figure 32-2a) and are associated with a poor prognosis.

Deletions of 17p13.3

The TP53 gene at 17p13.3 is deleted in 7% to 11% of CLL/SLL cases; it is best detected by FISH (illustration in Figure 32-2c) but is sometimes also detected by karyotyping. TP53 maintains genome integrity by orchestrating the repair or elimination of cells with damaged DNA and contributes to the cytotoxicity of many anticancer agents. It is therefore not surprising that TP53 dysfunction is associ ated with an adverse clinical outcome in CLL/SLL patients, as well as other BCLs.

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