Translocation t(1;6)(p35.3;p25.2) Involves RCC1 and IRF4 and Is Not Restricted to Unmutated Chronic Lymphocytic Leukemia

The disease course of B-cel chronic lymphocytic leukemia (CLL) is highly variable and genetic aberrations help to stratify patients with different prognosis. Therefore, detailed characterization of CLL associated chromosomal aberrations is important in order to identify patient subsets who need close monitoring and early therapy. The t(1;6)(p35.3;p25.2) involving IRF4 is extremely rare in CLL and has been associated with high-risk chromosomal aberrations [i.e. del(11q) and del(17p)], unmutated IGHV status and a rather progressive clinical course.

Here, we report the clinical, morphological and cytogenetic features of five new patients with a t(1;6)(p35.3;p25.2) and characterize for the first time the breakpoints at the molecular level.

Five patients with B-NHL and a t(1;6)(p36∼p33;p25∼p23) in the karyotype were included in the study. Immunophenotype and/or morphology corresponded with CLL in 4/5 cases. The fifth case presented with follicular lymphoma (FL). The t(1;6)(p35.3;p25.2) was confirmed by FISH in all cases.

When the 5 additional cases are considered together with 8 previously reported (Michaux et al., 2005), the female/male ratio is 3/10 with a median age of 63 (range 33–81). Four of the CLL patients presented with Binet stage A, 5 with stage B and 3 with stage C. Median leukocytosis was 11.8×10⁹/L (range 1.8–103×10⁹/L), LDH levels were elevated in 2 and CD38 was expressed in 7/9 patients. Nine patients showed an unmutated and 2 a mutated IGHV status (not available: n=2). Eleven patients required therapy, 0.5–62 months (median 0.5 month) after diagnosis. Only one of the 5 new cases was refractory to the therapy and died due to the disease after a follow-up of 20 months.

The t(1;6) was found as the sole karyotypic change in 2 cases and was associated with one abnormality in 2 other cases (i.e. a +12 and a +15). The case with FL showed a complex composite karyotype. In addition, FISH detected a cryptic del(11q) and del(17p) in one case each. The 1p breakpoint was mapped to a 500Kb region between BACs RP11–290H1 and RP11–442N24 and the 6p breakpoint into the BAC RP11–233K4.

Molecular analysis of 7 t(1;6) positive patients confirmed the presence of the translocation and demonstrated a fusion between the 5' end of RCC1 (in intron 1, 2 or 3) on 1p35, and IRF4 (in intron 1) on 6p25. The resulting fusion transcript consists of RCC1 exon 1, exon 2 or exon 3, linked to exon 2 of IRF4. In one patient, a 48 basepair long insert from intron 3 was present between RCC1 exon 3 and IRF4 exon 2. The first 4 exons of RCC1 are part of the 5'- untranslated region, whereas the open reading frame of IRF4 starts at exon 2. As such, the t(1;6) likely alters the expression of IRF4.

The RCC1 protein is widely expressed and is involved in chromatin condensation. IRF4 is a transcription factor with expression restricted to the immune system. The IRF4 protein plays a critical role in B-cell differentiation and mature T- and B-lymphocyte function. The t(6;14)(p25.2;q32) which juxtaposes IRF4 to the immunoglobulin loci (IG) resulting in IRF4 overexpression, has been reported in rare multiple myeloma (MM) cases and other mature B-NHLs. The oncogenic capacity of IRF4 has been demonstrated in MM. In CLL, the role of IRF4 remains unknown. Heterogeneous IRF4 expression has been observed between patients and examined tissues, and data on prognostic significance are conflicting. Here, we report 5 additional cases with t(1;6)(p35.3;p25.2) and demonstrate that this translocation is seen in unmutated CLL, as well as in mutated CLL and other indolent lymphoproliferative disorders. This is in contrast to the previously reported exclusive association of t(1;6) with unmutated CLL. At the molecular level, the t(1;6) results in a fusion transcript between RCC1 and IRF4 by which IRF4 expression is altered. Recognition of this and other translocations is important in order to refine the prognostic stratification of patients with CLL.

No relevant conflicts of interest to declare.