Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Chronic Lymphocytic Leukemia (CLL) [91.10]

OMIM numbers: 151400147070 (IGHV@), 301721 (BIRC3), 606278 (FBXW7), 612260 (MYD88), 190198 (NOTCH1), 605590 (SF3B1), 191170 (TP53), 602559 (XPO1)

Dipl.-Ing. (FH) Tanja Hinrichsen

Scientific Background

According to the nomenclature of the WHO, CLL is described as leukemic, lymphocytic lymphoma. It is characterized by progressive lymphocytosis that is caused by clonal accumulation of CD5+ and CD19+ B-cells in the peripheral blood, bone marrow and the lymphoid organs. With an incidence of 3:100,000/year, CLL is one of the most frequently occurring forms of leukemia. Mainly older people are affected; the clinical course is heterogeneous. While the disease is insidious in approx. 80% of all newly-diagnosed cases, 20% of all patients suffer from a progressive, aggressive clinical course. According to the Rai/Binet staging system, which is considered the basis for diagnosis and classification of CLL, the course of the disease cannot be predicted. Besides basic diagnostics such as differential blood count, cytochemistry and immunophenotyping, also genetic markers play an important role in establishing a prognosis.

From a molecular biological viewpoint, two aspects are of significance:

  1. Acquired, genomic aberrations that may be involved in the origin of the disease or determine the clinical course
  2. Mutational status of the immunoglobulin heavy chain variable region (IGHV) genes

While specific chromosome abnormalities can be detected with the conventional chromosome banding in 40-50% of all CLL cases, abnormalities can be found in more than 80% of all CLL patients using FISH on interphase cells. With a frequency of 40-60%, the most frequently occurring abnormality is the deletion of the band 13q14. It contains the micro RNAs miR15a and miR16-1 and, if present as the sole abnormality, is associated with a favorable course of the disease. A trisomy 12 (frequency 15-30%) and a normal karyotype are associated with an intermediate course. Deletions of the region 11q22.3 (frequency 15-20%), which contains the gene ATM, and the region 17p13 (frequency approx. 10%), which affects the gene TP53, are associated with an unfavorable course. Furthermore, in approximately 10% of all patients, TP53 mutations can be detected, which, just like the 17p13 deletion, are associated with an unfavorable prognosis. Patients with a deletion 17p13 or a TP53 mutation were, moreover, resistant to a standard chemotherapy with purine nucleoside analogs (e.g. fludarabine) or aliphatic agents (e.g. chlorambucil). Studies showed that these patients respond to a treatment with ibrutinib or idelalisib in combination with rituximab. Cytogenetic abnormalities may occur during the course of the disease. Therefore, regular control by FISH is recommended.

In addition, mutations in the NOTCH1 gene are found in approx. 11% of all CLL patients. These patients frequently exhibit an unmutated IGHV mutational status, a high expression of CD38 and ZAP-70 or a trisomy 12. Especially patients in Binet stage A and B with NOTCH1-mutated show shorter time to treatment. Furthermore, there is an increased risk for a transformation into a diffuse large B-cell lymphoma (DLBCL). Approximately 2-3% of patients show a mutation in the FBXW7 gene which activates the NOTCH1 signaling pathway.

In approx. 11% of CLL patients mutations in the SF3B1 gene are detected. Mutations in SF3B1 are associated with male sex, advanced clinical stage at diagnosis, unmutated IGHV mutational status and deletion 11q22.3.

Furthermore, 2-3% of CLL patients show mutations in the BIRC3 gene. These cases usually exhibit an advanced clinical stage at diagnosis and unmutated IGHV mutational status. So far the mutations were never associated with a deletion 17p13 but frequently with a deletion 11q22.3 or trisomy 12.

Mutations in the MYD88 gene are found in approx. 2% of CLL patients. They are associated with a mutated IGHV mutational status and isolated deletion 13q14.

In rare cases mutations can be found in the XPO1 gene.

Another important genetic marker is the IGHV mutational status. Normal B-cells have different receptors that are able to recognize every possible antigen. This variety in the immunoglobulin heavy chains (IgH) results from a combination of one of the approximately 51 V segments (variability) with one of the 27 D segments (diversity) and one of the six J segments (joining). After somatic recombination, the variability of the antibodies is further increased by the integration of somatic mutations into the IGHV sequence. The presence or absence of these somatic mutations in the IGHV region can be used in diagnostics to distinguish two entities of CLL. B-CLL is considered unmutated if an homology of ≥ 98% in IGHV respective to the germline sequence is present. While the hypermutated form of B-CLL has been associated with a favorable prognosis, the unmutated form has been associated with an unfavorable prognosis. The IGHV status exists already at the beginning of the disease and does not change during the course. B-CLL which uses the IGHV3-21 gene segment is an exception. An aggressive course with a short survival time has been observed in these cases despite somatic mutations. The ZAP70 expression and the CD38 expression (see chapter immunobiology) are thought to be surrogate markers for the IGHV mutational status; the correlation, however, is not absolute.