Coexistence of t(2;14;11)(p16.1;q32;q23) and t(14;19)(q32;q13.3) chromosome translocations in a patient with chronic lymphocytic leukemia

Abstract Rationale: With combination of multiple techniques, we have successfully characterized unique, complex chromosomal changes in a patient with chronic lymphocytic leukemia (CLL), a lymphoproliferative disorder. Diagnoses: The diagnosis was based on white blood cell, flow cytometry, and immunophenotypes and confirmed by karyotype, fluorescence in situ hybridization, and array comparative genomic hybridization from the patient's blood culture. Interventions: The patient was given fludarabine, cyclophosphamide and rituximab (FCR) for 6 cycles. Outcomes: After completion of 6 cycles of FCR, the computed tomography scans of the neck/chest/abdomen/pelvic showed that the patient in CR. During the 10-month follow-up, the patient's clinical course remained uneventful. Lessons: The translocation t(14;19) identified in this patient is a recurrent translocation found in patients with chronic B-cell lymphoproliferative disorders and the 3-way translocation involving chromosomes 2, 14, and 11 may play a role as an enhancer.

Fluorescence in situ hybridization (FISH) analyses were performed in the uncultured and cultured cells using the LSI IGH and LSI MLL dual color break-apart rearrangement probes (Abbott Molecular, Inc., Des Plaines, IL) and LSI BCL11A and LSI BCL3 dual color break-apart rearrangement probes (Empire Genomics, Inc., Buffalo, NY). The uncultured cells were also tested using CLL panel (Abbott Molecular, Inc., Des Plaines, IL). All the experimental procedures followed the manufacturers' instructions.
Further array comparative genomic hybridization (CGH) analyses on the patient's DNA sample revealed the presence of an extra chromosome 12 and deletion of 13q14.11-q21, which  was consistent with our karyotype analyses. Interestingly, we also found a gain of 4p16.2 (4,788,290-5,227,609 bp hg19; 0.4 Mb) containing MSX1 (msh homeobox 1) gene (Fig. 4), which plays a pivotal role in early hematopoietic development and malignancy transformation.
The MLL gene rearrangement often occurs in acute myelocytic leukemia (AML), acute lymphoblastic leukemia, and myelodysplastic syndrome. In hematologic malignancies such as CLL, the most common abnormality is the deletion of the MLL(11q23), [19] whereas the MLL gene rearrangement has not been previously observed in CLL. In this study, we revealed this interesting 3-way translocation of the MLL gene rearrangement; whether it contributes to the leukemia progression or even an unfavorable prognosis in CLL warrants further investigation.
It is widely believed that presence of only the IGH rearrangement is not sufficient to induce tumorigenesis, and acquisition of additional genetic aberrations is necessary for malignant transformation. [8] Trisomy 12, observed in this case, is one such genetic anomaly. The cytogenetic abnormality of trisomy 12 associated with intermediate prognosis is observed in up to 50% of IGH/BCL3-positive B-CLLs and was considered to act cooperatively with t (14;19) in leukemogenesis. [20] Interestingly, however, it was reported that patients with 13q deletions as a sole abnormality had the longest estimated survival times compared with other cytogenetic abnormalities. [4,21] Moreover, miR-15a and miR-16-1 locate in this region, and negatively regulate BCL2 expression at a posttranscriptional level. [22] MSX1 was found to be overexpressed in cell lines derived from MCL and leukemia AML as well as in 3% of patients with MCL and AML. [23] In the present study, array CGH revealed a cryptic gain of MSX1 gene besides trisomy 12 and del(13q14.11-q21), which has not been reported previously in CLL. These data suggest an oncogenic role for MSX1 in leukemogenesis.
In summary, we reported a rare case of an adult CLL patient with the coexistence of classical IGH/BCL3 translocation and a three-way variant translocation BCL11A/IGH/MLL, as well as trisomy 12 and del(13q). Furthermore, a cryptic genomic alteration involving leukemia-related MSX1 gene was found in this case at the level of the array CGH.