Chromosomal abnormalities involving 14q32 region are recurrently observed in B-cell neoplasms, particularly in non-Hodgkin lymphomas, multiple myeloma, B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia (CLL)¹. In CLL, some studies have shown that chromosome 14q32 translocations involving the immunoglobulin heavy chain gene (IGH) are frequently observed in conjunction with other FISH abnormalities and occur at a 5-15% incidence^2-4.

Immunoglobulins (Ig) are the antigen recognition molecules of B cells, which mediate the immune system performance. An Ig molecule is made up of 2 identical heavy chains and 2 identical light chains (Figure 1) joined by disulfide bonds so that each heavy chain is linked to a light chain, and the 2 heavy chains are linked together. The amino terminal ends of the polypeptide chains show considerable variation in amino acid composition and are referred to as the variable (V) regions to distinguish them from the relatively constant (C) regions. Each light chain consists of one variable domain, VL, and one constant domain, CL. The heavy chains (IGH) consist of a variable domain, VH, and three constant domains CH1, CH2 and CH3 (from Antibodies. A Laboratory Manual by E Harlow and D Lane, 1988). It is noteworthy to mention that IGH gene is clinically relevant in CLL, since the mutational status of its variable chain (IGHV) represents one of the most powerful prognostic markers⁵.

 Figure 1. Diagram of immunoglobulin structure (from Antibodies. A Laboratory Manual by E Harlow and D Lane, 1988)

Translocations represent the juxtaposition of fragments of DNA that are usually in different chromosomes. While some genes rearranged only with one partner gene, others show high promiscuity in their translocations, with multiple possible partners. The latter is the case of the immunoglobulin (IG) loci-involved rearrangements⁶. The cloning of the genes located at the breakpoints of chromosomal translocations in leukemia and lymphoma has led to the identification of new genes involved in carcinogenesis. Translocations involving the IGH/14q32 region relocate genes near an active regulatory sequence, leading to their overexpression. Most common relocated gene in CLL is BCL2 in t(14;18)(q32;q21) (Figure 2), which is found in ~2% of cases, all belonging to the IGHV-mutated subgroup⁷. This gene encodes an integral outer mitochondrial membrane protein that blocks the apoptotic death of some cells, such as lymphocytes. Other sporadic partners in IGH translocations are CCND1 in t(11;14)(q13;q32), MYC in t(8;14)(q24;q32), BCL3 in t(14;19)(q32;q13), BCL11A in t(2;14)(p13;q32), CCND3 in t(6;14)(q21;q32) or CDK6 in t(7;14)(q21;q32)^8,9.

Figure 2. IGH translocation with BCL2 gene (t(14;18))¹⁰.

Clinical impact of IGH rearrangements in CLL patients is still controversial. In some studies, prognosis appears to be poor in the presence of these translocations, with the exception of t(14;18)³. Cavazzini et al. observed that this cytogenetic subset had a worse clinical course compared to CLLs with favorable or intermediate-risk cytogenetics⁹. Furthermore, no difference was observed in terms of time to first treatment (TFT) and overall survival (OS) depending on the presence or absence of t(14;18), or the presence of chromosome aberrations in addition to the IGH translocation. However, Davids et al. demonstrated that TFT was significantly shorter among CLL patients harboring 14q32 translocations without t(14;18), compared with those with t(14;18)¹¹, which was consistent with the results obtained in more recent studies^12,13.

This controversy could be explained by different factors, including the small number of cases with these translocations, the frequent association of 14q32 translocations with additional cytogenetic aberrations, the inclusion of patients with t(11;14) that may be cases of mantle cell lymphoma and the possibility that a fraction of CLL with t(14;18) may actually be leukemic forms of follicular lymphoma^9,13,14.

In terms of molecular features, IGH translocation have been previously related to NOTCH1 mutations and trisomy 12^14,15. A recent study has characterized the genetic landscape of CLL patients with 14q32/IGH translocations by next-generation sequencing (NGS), demonstrating that IGH-rearranged CLLs have a distinct mutational profile from other classic cytogenetic groups of CLLs, and also dependent on whether BCL2 is involved or not in the IGH rearrangement (Figure 3)¹³. Patients with IGH rearrangements exhibited a high mutational frequency in NOTCH1, BCL2, FBXW7, ZMYM3, MGA and BRAF with respect to the rest of CLLs. Moreover, patients with t(14;18) were enriched in BCL2 and IGLL5 mutations, while IGH translocations with other partners had higher mutational frequencies in NOTCH1, TP53 or FBXW7. Interestingly, the presence of these genetic mutations have a negative clinical outcome in this subgroup of patients, refining their prognosis¹³.

Figure 3. Mutational profile of CLL patients with IGH translocations¹³.