Positive Chronic Lymphocytic Leukemia Research Articles

T(14;19)(q32;q13): a recurrent translocation in B-cell precursor acute lymphoblastic leukemia.

The recurrent t(14;19)(q32;q13) translocation associated with chronic B-cell lymphoproliferative disorders, such as atypical chronic lymphocytic leukemia, results in the juxtaposition of the IGH@ and BCL3 genes and subsequent overexpression of BCL3. We report six patients with B-cell precursor acute lymphoblastic leukemia who have a cytogenetically identical translocation with different breakpoints at the molecular level. Fluorescence in situ hybridization with locus-specific probes confirmed the involvement of the IGH@ gene but showed that the breakpoint on 19q13 lay outside the region documented in t(14;19)(q32;q13)-positive chronic lymphocytic leukemia. This newly described translocation constitutes a distinct cytogenetic subgroup that is confined to older children and younger adults with B-cell precursor acute lymphoblastic leukemia.

Author reply

We read with great interest the letter by Imashuku et al. regarding our recent description of hemophagocytic syndrome with Epstein–Barr virus (EBV) negative B-cell lymphomas.1 Although we could not differentiate the pattern of hypercytokinemia among the data in our hands, Imashuku et al. observed significantly higher levels of serum interferon-γ (IFN-γ) concentrations in T-cell lymphoma-associated hemophagocytic syndrome (T-LAHS) when compared with B-cell lymphoma-associated hemophagocytic syndrome (B-LAHS). The result was extracted from the huge accumulation of their data regarding hemophagocytic syndrome (HPS).2-4 The majority of their T-LAHS cases were EBV-related, whereas B-LAHS cases were not. Although we should be careful concerning the age difference, their observation provides an important clue in understanding the difference in the pathogenesis of HPS between T-LAHS and B-LAHS. In B-LAHS cases, as well as angioimmunoblastic lymphadenopathy with dysproteinemia and pleomorphic T-cell lymphoma of angioinvasive type in T-LAHS, a histologic predisposition may exist. The majority of histologically proven cases are intravascular lymphomatosis.1, 5 These are followed by T-cell rich B-cell lymphomas and those simply documented as diffuse large cell type. Thus, nearly all B-LAHS cases are considered to constitute a unique subtype of diffuse large B-cell lymphomas. It is interesting to note that, in this subtype, many reactive cells, including lymphocytes, histiocytes, and endothelial cells, are intermingled with systemically disseminated but relatively few neoplastic cells. In such a case, hypercytokinemia in B-LAHS may not be ascribed to the neoplastic cells themselves. Conversely, interleukin (IL)-2 and IL-6 are well known to be B-cell helper factors that also are elaborated by B cells themselves. Although INF-γ may exhibit some helper activity and delay apoptosis of CD5 positive chronic lymphocytic leukemia cells, evidence that B cells produce IFN-γ has not been accumulated.6, 7 Thus, we assume that intervening, reactively activated, nonneoplastic T cells may be responsible for the induction of B-LAHS, in which the magnitude of increased INF-γ is relatively low compared with T-LAHS, as Imashuku et al. have described. Tatsuharu Ohno M.D.*, * Division of Hematology and Immunology Department of Internal Medicine Ohtsu Red Cross Hospital Shiga, Japan

CD5 positive breast carcinoma in a patient with untreated chronic lymphocytic leukaemia: molecular studies of chromosome 13q.

A 67 year old woman presented with a right breast lump which proved to be a grade 2 invasive ductal carcinoma with axillary lymph node metastasis. She had a five...

Effect on cell kill of addition of multidrug resistance modifiers cyclosporin A and PSC 833 to cytotoxic agents in chronic lymphocytic leukaemia

Expression of P-glycoprotein (Pgp), the drug efflux pump which mediates multidrug resistance (MDR), has been widely reported in chronic lymphocytic leukaemia (CLL) and improved accumulation of daunorubicin has been reported using the MDR reversing agent cyclosporin A (CSA). We have investigated the effects on cell kill of the addition of CSA and its analogue PSC 833 to daunorubicin, doxorubicin, idarubicin, mitozantrone and fludarabine in samples from 51 patients with CLL using an MTT [3(4,5-dimethylthaizol-2-yl)-2,5-diphenyltetrazolium bromide] assay. Pgp expression was assessed by immunocytochemistry using the JSB-1 monoclonal antibody. Of the 51 samples, 10 (20%) were Pgp positive and all of these samples were from treated patients. With the exception of mitozantrone, the addition of CSA and PSC 833 to cytotoxic agents failed to significantly improve cytotoxicity, even in the Pgp positive group. With mitozantrone significant responses were seen in both Pgp positive and negative groups suggesting that the responses were due to direct cytotoxicity of the cytotoxic–modifier combination rather than reversal of MDR. Both CSA and PSC 833 showed significant direct cytotoxicity ( P=0.004 and 0.04 for PSC 833 at 1000 ng/ml and 500 ng/ml respectively; P<0.001 for both concentrations of CSA). The responses were disappointing compared to the highly significant improvements in cytotoxicity seen using cells from the Pgp positive CEM VLB 100 acute myeloid leukaemia cell line, and it was not possible to demonstrate the superiority of PSC 833 over CSA which is also seen in cell lines. Our data do not support a role for Pgp modifiers in CLL. Further studies using larger numbers of Pgp positive CLL cells and higher doses of PSC 833 would be useful.

Detection of t(11;14) using interphase molecular cytogenetics in mantle cell lymphoma and atypical chronic lymphocytic leukemia.

The chromosomal translocation t(11;14)(q13;q32) fuses the IGH and CCND1 genes and leads to cyclin D1 overexpression. This genetic abnormality is the hallmark of mantle cell lymphoma (MCL), but is also found in some cases of atypical chronic lymphocytic leukemia (CLL), characterized by a poor outcome. For an unequivocal assessment of this specific chromosomal rearrangement on interphase cells, we developed a set of probes for fluorescence in situ hybridization (FISH). Northern blotting was performed for analysis of the cyclin D1 expression in 18 patients. Thirty-eight patients, with either a typical MCL leukemic phase (17 patients) or atypical CLL with an MCL-type immunophenotype, i.e., CD19-, CD5+, CD23-/low, CD79b/sIgM(D)++, and FMC7+ (21 patients), were analyzed by dual-color interphase FISH. We selected an IGH-specific BAC probe (covering the JH and first constant regions) and a commercially available CCND1 probe. An IGH-CCND1 fusion was detected in 28 of the 38 patients (17 typical MCL and 11 cases with CLL). Cyclin D1 was not overexpressed in two patients with typical MCL and an IGH-CCND1 fusion. In view of the poor prognosis associated with MCL and t(11;14)-positive CLL, we conclude that this set of probes is a valuable and reliable tool for a rapid diagnosis of these entities.