Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial.

BACKGROUND: Previous studies of patients with chronic lymphocytic leukaemia reported high response rates to fludarabine combined with cyclophosphamide. We aimed to establish whether this treatment combination provided greater survival benefit than did chlorambucil or fludarabine. METHODS: 777 patients with chronic lymphocytic leukaemia requiring treatment were randomly assigned to fludarabine (n=194) or fludarabine plus cyclophosphamide (196) for six courses, or chlorambucil (387) for 12 courses. The primary endpoint was overall survival, with secondary endpoints of response rates, progression-free survival, toxic effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number NCT 58585610. FINDINGS: There was no significant difference in overall survival between patients given fludarabine plus cyclophosphamide, fludarabine, or chlorambucil. Complete and overall response rates were better with fludarabine plus cyclophosphamide than with fludarabine (complete response rate 38%vs 15%, respectively; overall response rate 94%vs 80%, respectively; p<0.0001 for both comparisons), which were in turn better than with chlorambucil (complete response rate 7%, overall response rate 72%; p=0.006 and 0.04, respectively). Progression-free survival at 5 years was significantly better with fludarabine plus cyclophosphamide (36%) than with fludarabine (10%) or chlorambucil (10%; p<0.00005). Fludarabine plus cyclophosphamide was the best combination for all ages, including patients older than 70 years, and in prognostic groups defined by immunoglobulin heavy chain gene (V(H)) mutation status and cytogenetics, which were tested in 533 and 579 cases, respectively. Patients had more neutropenia and days in hospital with fludarabine plus cyclophosphamide, or fludarabine, than with chlorambucil. There was less haemolytic anaemia with fludarabine plus cyclophosphamide (5%) than with fludarabine (11%) or chlorambucil (12%). Quality of life was better for responders, but preliminary analyses showed no significant difference between treatments. A meta-analysis of these data and those of two published phase III trials showed a consistent benefit for the fludarabine plus cyclophosphamide regimen in terms of progression-free survival. INTERPRETATION: Fludarabine plus cyclophosphamide should now become the standard treatment for chronic lymphocytic leukaemia and the basis for new protocols that incorporate monoclonal antibodies.

IgVH genes mutation and usage, ZAP-70 and CD38 expression provide new insights on B-cell prolymphocytic leukemia (B-PLL).

B-prolymphocytic leukemia (B-PLL) is a rare disease with poor prognosis. To further characterize the biological features of this disease, we analyzed immunoglobulin heavy chain (IgVH) mutations, ZAP-70 and CD38 in 19 cases with de novo B-PLL. Immunoglobulin heavy chain genes analysis showed an unmutated pattern (>98% homology to germ line) in 9/17 cases (53%), with 100% homology in eight. In the remaining, it ranged from 90 to 97.4%, with three cases slightly mutated (98-95%) and five heavily mutated (<95%). All B-PLL utilized members of VH3 (11/17) and VH4 (6/17) families, with V3-23, V4-59 and V4-34 gene accounting for more than half of them, regardless of mutational status. ZAP-70, assessed by flow cytometry, ranged from 1 to 91% cells, being > or =20% in 57% of cases. CD38 ranged from 1 to 99% (median 21%). There was no correlation between IgVH status and ZAP-70 or CD38 expression, but male gender and del(17p) were more common in the unmutated group. Neither IgVH mutations, CD38 expression nor del(17p) influenced patients' outcome. Unexpectedly, ZAP-70+ B-PLL patients survived longer (40 months) than ZAP-70- B-PLL (8 months). B-PLL appears biologically heterogeneous regarding IgVH mutations, ZAP-70 and CD38 expression, showing a pattern distinct from that of other lymphoproliferative disorders.

ATM is usually rearranged in T-cell prolymphocytic leukaemia.

T-prolymphocytic leukaemia (T-PLL) is a rare, sporadic leukaemia similar to a mature T-cell leukaemia seen in some patients with Ataxia Telangiectasia (A-T), a recessive multisystem disorder caused by mutations of the ATM gene at chromosome 11q23. ATM sequence mutations have been reported in 46% of T-PLL cases, but some cases also have karyotypic abnormalities at 11q, including 11q23. This led us to investigate the structure of the ATM locus in a panel of eight cases, two of which had 11q23 abnormalities. As expected, nucleotide changes were detected in some samples. Two remission samples were wild type. To test for structural lesions, DNA fibres were hybridized with a contig of four labelled cosmids spanning the ATM locus. In all samples there were structural lesions and in four samples both alleles were affected. This provides strong evidence for our suggestion that ATM acts as a tumour suppressor during T-PLL tumorigenesis. Some additional role for ATM during T-PLL tumorigenesis is possible since nucleotide changes were present in addition to structural lesions disrupting both alleles. The mechanism of inactivation appeared to be unusual because multiple structural lesions on one allele were often observed.

A t(8;14)(q24;q32) in a T-lymphoma/leukemia of CD8+ large granular lymphocytes.

Chromosome studies in a case of T cell lymphoma/leukemia, in which a high proportion of the dividing cells had a t(8;14)(q24;q32) similar to that seen in Burkitt's lymphoma, are described. The tumor cells had a mature T cell phenotype (TdT-,CD3+,CD8+,CD4-) and were morphologically large granular lymphocytes and immunoblasts, both cell types with similar lysosomal granules in the cytoplasm. The immunoglobulin heavy chain gene and the T cell receptor beta chain gene were not rearranged, while the T cell receptor gamma chain gene was polyclonally rearranged. Mitoses were obtained only from spontaneously dividing cells in the absence of mitogens; 49 of the 50 metaphases analyzed were chromosomally abnormal and had a t(1;22)(q12;q13) and dup(1)(q31q32) in all of them; 48 metaphases had in addition a t(8;14)(q24;q32) which presumably arose during clonal evolution. The latter may be associated with the aggressive behavior of this T cell disorder by comparison with other proliferations of large granular lymphocytes. Although abnormalities involving 14q32 are characteristic of B cell disorders, they have also been described in T cell malignancies, suggesting that genes transcribed in T cells and/or oncogenic sequences significant in T cell neoplasia are present in 14q32.

Translocations t(14;18) and t(8;14) with rearranged bcl-2 and c-myc in a case presenting as B-ALL (L3).

Follicular lymphoma is a low grade malignancy characterized by the translocation t(14;18), which involves the putative oncogene bcl-2. We describe a 73-year-old patient presenting with Burkitt acute lymphoblastic leukemia (B-ALL) L3 (Burkitt type), whose cells had the following immunophenotype: CD19+, CD22+, HLA-DR+, CD10+, TdT-, Cyt IgM-, CD34-. Analysis of 25 peripheral blood metaphases showed the presence of t(14;18) (q32;q21), and t(8;14) (q24;q32) in 24 cells and t(14;18) only in one cell, suggesting that the latter translocation came first during clonal evolution. Both bcl-2 and c-myc were rearranged in addition to the immunoglobulin heavy and light chain genes. The presence of small lymphoid cells in paratrabecular areas on the bone marrow biopsy, together with evidence of cytogenetic clonal evolution, was indicative of a transformation from a low grade follicular lymphoma to a more aggressive Burkitt type malignancy.

FISH analysis for BCL-1 rearrangements and trisomy 12 helps the diagnosis of atypical B cell leukaemias.

We have investigated the diagnostic value of fluorescence in situ hybridisation (FISH) to detect t(11;14) and trisomy 12 in 53 cases with a B cell leukaemia difficult to classify on clinical and laboratory grounds. These cases were initially diagnosed by morphology and immunophenotype and in 33 of them, on tissue histology, as follows: chronic lymphocytic leukaemia (CLL), 20, 18 of them with atypical features; B cell prolymphocytic leukaemia (B-PLL), two; mantle-cell lymphoma (MCL), 15; splenic lymphoma with villous lymphocytes (SLVL), five; lymphoplasmacytic lymphoma, six; follicular lymphoma, one and, four cases remained unclassifiable. FISH demonstrated BCL-1 rearrangement in the circulating cells from 15 cases classified as: MCL (10), atypical CLL (three) and B-PLL (two). A definitive diagnosis of MCL was made on review of the spleen histology in one out of the three atypical CLL with BCL-1 rearrangement. Trisomy 12 was detected in eight cases which included four atypical CLL, one typical CLL, two MCL and one unspecified B cell lymphoma by histology and morphology. One of the MCL had both trisomy 12 and BCL-1 rearrangement and the other was CD5+, CD23+ and had a CLL score of 3, suggesting the latter diagnosis. Our findings demonstrate that FISH analysis is useful to clarify the nature of the disease in patients presenting with a B cell leukaemia in which the diagnosis is difficult by conventional methods. FISH established with certainty the diagnosis of MCL by showing BCL-1 rearrangement in over two-thirds of cases in which this was suspected, including blastoid forms, and confirmed the diagnosis of most cases of atypical CLL.

Expression of c-myc oncoprotein in chronic T cell leukemias.

T cell clones in patients with ataxia telangiectasia (AT) and T cell prolymphocytic leukemia (T-PLL) have identical chromosome abnormalities, namely inv(14)(q11q32), t(14;14)(q11;q32) and t(X;14)(q27;q11). In T-PLL and AT developing T cell leukemia, the above abnormalities occur frequently together with trisomy for 8q. We postulated that the additional abnormalities of chromosome 8, where the c-myc oncogene is mapped to 8q24, may play a role in the development of overt leukemia. DNA analysis using the CD1A c-myc probe did not reveal rearrangements of the c-myc gene by Southern blotting. We have used a monoclonal antibody for the c-myc protein to investigate the level of expression in 11 patients with T-PLL and two with Sezary cell leukemia and compared it with levels seen in normal lymphocytes. Significantly higher levels were observed in patients compared with controls (P < 0.0001). The highest levels of c-myc were seen in eight cases with trisomy for 8q resulting from an i(8q). One patient was investigated before and after treatment. In the active state, c-myc showed a level of 64.36 units (range 20-200). After treatment a residual population of malignant cells showed a c-myc level of 155 (range 90-280). This study suggests that the increased expression of c-myc as a result of trisomy for 8q may have a role in the pathogenesis of de novo T-PLL and T cell leukemia supervening AT and that there may be a correlation between c-myc levels and resistance to therapy.

Sezary cell leukaemia: a distinct T cell disorder or a variant form of T prolymphocytic leukaemia?

We report the clinical, ultrastructural, immunophenotypic and virological features of nine cases of a rare type of mature T cell disorder formerly designated Sezary cell leukaemia. All patients presented with lymphocytosis ranging from 12.7 to 133 x 10(9)/l, bone marrow infiltration, splenomegaly and lymphadenopathy. Skin involvement was absent at presentation but developed as a terminal event in two patients, one of whom showed a pattern of dermal infiltration different from that characteristic of Sezary syndrome. Cells from eight cases bore a mature T cell phenotype and electronmicroscopy revealed lymphocytes with cerebriform nuclei resembling Sezary cells. All cases except one were HTLV-I negative. Patients were treated with various chemotherapy regimens but with poor outcome, the median survival being 13 months. Laboratory and clinical data suggest great similarity between Sezary cell leukaemia and T prolymphocytic leukaemia (T-PLL), namely coexpression of CD4 and CD8 (3/9 cases), identical chromosomal abnormalities in the three cases studied (isochromosome 8q plus inversion 14 or t(X;14)(q28;q11)) and a remarkable sensitivity to CAMPATH-1H (complete remission of 21 months' duration in one patient), suggesting that this entity could be considered a variant form of T-PLL. The alternative diagnosis of adult T cell leukaemia/lymphoma could not be excluded in one patient in whom positive HTLV-I serology was documented.

B cell prolymphocytic leukaemia (B-PLL) with complex karyotype and concurrent abnormalities of the p53 and c-MYC gene.

We report the cytogenetic, molecular and biological characterization of a case of B-PLL with a complex karyotype and concurrent abnormalities on the p53 and c-MYC genes. Conventional cytogenetics suggested that both 17q arms were translocated to chromosomes 1q and 14p, respectively, whereas both 17p arms were not identified. In addition, a Burkitt's-like variant translocation t(2;8) was found. Study of loss of heterozygosity at 17p13 and p53 direct sequencing demonstrated the presence of only one copy of the p53 gene. A 27 bp deletion in exon 8 that resulted in the expression of a p53 protein lacking nine amino acids from the DNA binding region was also found. To confirm the presence of one copy of the p53 gene and localize it, fluorescent in situ hybridization (FISH) studies using a p53 gene probe was performed. Only one signal of p53 was visualized. Moreover, the DAPI profile of the chromosome containing the hybridization spot for the p53 probe did correspond to the cytogenetic marker identified as der(14)t(14;17). Whole chromosome 14 paint, centromere-specific for chromosome 17 and p53 gene probes were cohybridized to the preparations. This demonstrated that the der(14) contained the 17 centromere and distally the p53 gene suggesting that the der(14) contained the short arm of chromosome 17 with the breakpoint occurring in the long arm. FISH studies confirmed the involvement of c-MYC and KAPPA in the t(2;8) translocation. To our knowledge, this is the first case of B-PLL with inactivation of the p53 gene by mutation together with a Burkitt's-like t(2;8) translocation involving the c-MYC gene. The cooperation of these genes may have conferred a growth advantage which was critical in the development of this aggressive form of B-PLL.

p53 gene deletion and trisomy 12 in hairy cell leukemia and its variant.

The deletion or mutation of the p53 tumour suppressor gene on chromosome 17p13 is known to be associated with aggressive disease in several B-cell malignancies. The present study describes the p53 gene status in 20 cases of hairy cell leukemia (HCL) and in 12 cases of its morphological variant (HCL-V) by fluorescence in situ hybridization (FISH). A high incidence of p53 deletion was found in both diseases (75-100% of cases). However, a significant difference was observed between the proportion of cells with p53 deletion in HCL-V cases (mean 31%) and HCL cases (mean 12%) P value < 0.01. The observed difference correlates with the well known tendency for transformation and poor response to therapy in HCL-V and seven cases of HCL-V with greater than 22% of cells with p53 deletion showed features of disease progression and transformation. Trisomy 12 was present in 8.5% of the cells in one case of HCL-V and in 6-8% of cells in three cases of HCL.

The 14q+ marker in hairy cell leukaemia. A cytogenetic study of 15 cases.

Leukaemic cells from 19 patients with hairy cell leukaemia (HCL), characterised by morphological, immunological and ultrastructural criteria, were investigated for chromosome abnormalities after stimulation with B-cell mitogens (Pokeweed mitogen (PWM), lipopolysaccharide B and EBV). The cells from all cases had a B-cell phenotype and in each case only a single light chain type was expressed on the membrane of the cells. Only 15 patients with adequate metaphases are included in this study. Clonal chromosome abnormalities were observed in 12 patients of which five had a 14q + involving q32. Of the remaining 3 cases 1 had nonclonal abnormalities and 2 had normal karyotypes. The donor chromosomes were identified in 3 cases and were found to be 9, 18 and 22. An interstitial rearrangement of chromosome 14 involving band q22 was seen in 2 cases and a deletion of chromosome 14 at q24 in 1 case. Amongst other chromosome abnormalities 12p was involved in 4 cases, 12q in 2 cases and chromosomes 7 and 22 in 3 cases each. The significance of the abnormalities has been discussed in relation to sites of cellular oncogenes. Our study demonstrates that chromosome abnormalities common to other B-cell disorders are present in HCL.

Inversions and tandem translocations involving chromosome 14q11 and 14q32 in T-prolymphocytic leukemia and T-cell leukemias in patients with ataxia telangiectasia.

Ataxia telangiectasia (AT) and T-prolymphocytic leukemia (T-PLL) have similar chromosome abnormalities. Cytogenetic findings reported in 5 patients with AT who developed T-cell leukemia revealed: inv(14)(q11q32) (1 case), tandem translocations of chromosome 14 with breakpoints at q11 and q32 (3 cases), and int. del(14)(q11q32) (1 case). Additional abnormalities were present in 4 patients of whom two had trisomy for 8q. Of 27 patients with T-PLL but without AT, investigated by us, 17 had inv(14)(q11q32) and 3 had tandem rearrangement of chromosome 14 with breaks at 14q11 and q32; 15 of them also had rearrangements resulting in trisomy 8q. Two of the leukemias supervening on AT had morphology and clinical course suggestive of T-PLL. Two other cases of AT studied by us developed typical T-PLL at a young age (18 and 39 years). T-cell clones carrying an inv(14), tandem t(14;14) and t(X;14) can be present in AT for long periods of time without evolving into leukemia. In T-PLL, inv(14) and t(14;14) always occurs with other chromosome abnormalities. We suggest that these additional chromosome abnormalities may be required for the leukemic transformation of AT. This is supported by one of the two AT cases studied by us in which a long-standing t(X;14) clone evolved with the formation of t(1;14)(p21;q11), t(8;22)(q24;q11) at the time of the development of T-PLL.

Break points in chromosome #1 abnormalities of 218 human neoplasms.

A survey of 343 break points that lead to chromosome #1 abnormalities in 218 human neoplasms showed that 49.9% were located in or immediately adjacent to the centromeric heterochromatin. Amongst rearrangements with breaks in bands p 12-q21 were 27 isochromosomes, 22 translocations of the long arm, and four translocations of the short arm to the heterochromatic regions of other chromosomes, and 35 deletions resulting in chromosomes consisting mainly or solely of one arm. Deletions following breakage at various sites in the short arm of chromosome #1 are frequent in malignancies and are quite often found in cells that are trisomic for the long arm. It is suggested that fragility of chromosomes generated as a result of early events in carcinogenesis may be one source of chromosome rearrangements, including those of chromosome #1, on which selection can operate and give rise to progressively more malignant clones.

Chromosome 1 heterochromatin variants and cancer: a reassessment.

Evidence for a relationship between chromosome #1 heterochromatin polymorphisms and cancer has been reviewed. Eighty-four of 135 (62%) patients with epithelial malignancies were heteromorphic for C-band size compared with 38 of 107 (36%) controls (significant at the 0.1% level). However, only 33 of 67 (49%) patients with nonepithelial malignancies were heteromorphic (not significantly different from controls). Similarly, the incidence of partial inversions of the C-band region in one or both homologs was significantly greater than controls [28 of 107 (26%)] for patients with epithelial [66 of 135 (49%)] but not nonepithelial [25 of 67 (37%)] malignancies. However, when the presence of either or both size heteromorphism and inversions were assessed, the incidence was significantly higher in patients with nonepithelial [46 of 67 (69%), including 11 of 11 patients with leukemia or myeloproliferative disorders] as well as epithelial [112 of 135 (83%)] malignancies compared with controls [52 of 107 (49%)]. Forty-seven of the patients did not differ significantly from controls with respect to the incidence of chromosome #1 heteromorphism as revealed by the Giemsa-11 technique. However, 26 patients assessed for their chromosome #1 lateral asymmetry pattern differed significantly from controls, having a higher incidence of compound asymmetry with a large proximal and small distal block and a lower incidence of simple asymmetry.

Three or four copies of a dicentric 17q isochromosome in an acute myeloproliferative disorder.

The majority of metaphases in the bone marrow of a male patient aged 72 with a rapidly evolving aleukemic erythremic myelosis had 48 chromosomes with three copies, or 49 chromosomes with four copies, of an i(17q), which was seen to be dicentric in C-banded and Giemsa-11-banded preparations. There was also loss of a chromosome No. 5 and the addition of a chromosome resembling a No. 22. The presence of multiple copies of the isochromosome is postulated to be related to the acuteness of the condition.

Cytogenetic abnormalities in the leukemic phase of non-Hodgkin lymphoma.

We have carried out chromosome analysis in a series of 16 non-Hodgkin Lymphoma (NHL) cases in leukemic phase. The diagnoses in these patients based on histology and immunologic markers were as follows: follicular lymphoma (FL), 3 cases; mantle cell lymphoma (Mc), 4 cases; lymphoplasmacytic lymphoma (LPL), 8 cases, and large cell lymphoma, 1 case. We have shown that the t(14;18), t(11;14), and trisomy 12 retained their subtype association with FL, Mc, and LPL, respectively, as in their nonleukemic counterparts with one case of FL showing t(1;19)(q23;p13). Among the four LPL cases without trisomy 12, one case each showed t(12;14)(q13;q32), trisomy 14, t(1;3)(p34;q21), and del(3)(q21). The t(1;19) and t(12;14) may represent rare events in FL and LPL, respectively, and may be uniquely associated with the leukemic phase. The breakpoint 14q32 was the most common single breakpoint involved, sometimes involving both chromosome 14 homologues depicting its association with primary and secondary genetic events in the disease progression. In addition to the main abnormalities, we have shown additional complex abnormalities in 14 of 16 cases. Among these, chromosome 3 was the most commonly involved, affecting the short or long arm or the whole chromosome; 5 of the 16 cases involved breakpoint 3q21. The high incidence of additional abnormalities in these NHL in leukemic phase suggest an association with the development of leukemia and progression of the disease.

Unusual breakpoint distribution of 8p abnormalities in T-prolymphocytic leukemia: a study with YACS mapping to 8p11-p12.

Chromosome 8 abnormalities are seen in 80% of patients with T-cell prolymphocytic leukemia (T-PLL). The abnormalities described are idic(8)(p11),t(8;8)(p11;q12),+8, and 8p+ with the involvement of 8p. To localize 8p11-p12 breakpoints in T-PLL, metaphases from seven cases were karyotyped. Those with idic(8)(p11) and add(8)(p11) were probed with a panel of contiguous YACs derived from 8p11-p12 using fluorescence in situ hybridization (FISH). Analysis of FISH results showed that 8p11-p12 breakpoints cluster into two regions. The first region is telomeric to YAC 899e2, which contains the fibroblast growth factor receptor-1 gene (FGFR1) and appears to cluster within a 1.5-MB YAC 807a2. The second region is more centromeric with breakpoints on either side of YAC 806e9, flanked by YAC 940f10 distally and YAC 910d7 proximally, the latter containing the MOZ gene. These findings showed that a segment of 8p was still present in the isodicentric, but the pattern of clustering does not seem to correspond to a breakpoint affecting a single gene. The clustering regions are likely to be hot spots for recombination and result in idic(8)(p11) and 8p+. These changes point to the pathogenesis of T-PLL involving deletion of a gene sequence on 8p and/or gain of a copy of 8q.

Adult T-cell lymphoma/leukemia in a Caribbean patient: cytogenetic, immunologic, and ultrastructural findings.

Cytogenetic findings on immunologically and morphologically characterized leukemic cells from a Caribbean patient with adult T-cell lymphoma/leukemia (ATLL) (HTLV+) are reported. Marker studies on peripheral blood lymphoid cells showed a mature postthymic phenotype: TdT-, OKT3+, OKT4+, OKT6-, OKT8-, 3A1-, anti-HLA-DR-. Light and electron microscopic analysis revealed a great cellular pleomorphism with respect to nuclear features. Three main types of leukemic cell were observed: typical multilobed ATLL lymphocytes, Sézary's syndrome (SS) cells, and cells intermediate between those two. Chromosome studies on PHA-stimulated cultures revealed three clones. The predominant clone was hyperdiploid; significant abnormalities were 1q+, 14q+, and 6q- (breakpoint q21), which are known to occur in lymphoid malignancies, together with trisomy 7q and i(17q), which have been reported previously in Japanese ATLL and the small variant of SS, respectively. The 14q+ marker was t(11;14)(q13;q22-24). The incidence of 6q-, trisomy 7q, and i(17q) varied within the main clone, and it is speculated that these chromosome abnormalities might be related to the variation observed in the cell types of this patient. Two minor clones had 6q- (breakpoint q25) and 13q+ markers, respectively. It was not possible to unequivocally establish the relationship between these three clones. The chromosomal, morphologic, and immunologic findings in this case support a close relationship between ATLL in Japan and in the Caribbean basin, as well as between the proliferating cells of ATLL and SS.

Abnormalities of chromosomes 8, 11, 14, and X in T-prolymphocytic leukemia studied by fluorescence in situ hybridization.

Twenty-one patients with T-prolymphocytic leukemia (T-PLL) were studied by FISH to characterize abnormalities of chromosomes 8, 11, 14, and X. A higher percentage of abnormalities of these chromosomes was detected by FISH than by cytogenetics. Seventy-one percent had inv(14) (q11q32)/t(14;14)(q11;q32). Four patients had abnormalities involving Xq28 (MTCP-1 locus) resulting from t(X;14)(q28;q11) or t(X;7)(q28;q35). These abnormalities have also been described in persistent expanding pre-malignant T-cell clones in patients with ataxia telangiectasia (AT). We have previously reported that in T-PLL and AT developing T-cell leukemia, the above abnormalities occur with additional abnormalities, mainly trisomy for 8q resulting predominantly from an i(8)(q10) and an increased expression of MYC. In this series, 81% of cases had chromosome 8 abnormalities including i(8)(q10)[43%]/t(8;8)(p12;q11)[14%], + 8[14%], and 8p + [14%]. The use of probes for MYC (8q24) and chromosome 8 centromere on metaphase chromosomes revealed that cases with i(8)(q10) were dicentric and t(8;8) monocentric. These abnormalities are not only associated with increase in dosage of 8q and the MYC gene, but also involved 8p. 8p is known to have several suppressor genes associated with solid tumors. Our findings suggest that the possible loss of a tumor suppressor gene plus the increased dosage of the q arm and/or the high expression of TCL-1/MTCP-1, which results from inv(14)/t(14;14), allows the malignant phenotype to emerge.

Two unbalanced translocations, t(12;22)(p13;q11) and t(12;?)(p13;?), in an aggressive chronic B-cell leukemia: TEL gene analysis using FISH.

The translocation t(12;22)(p13;q11) has been consistently described in myeloid malignancies and shown to result from a fusion between the TEL and MN1 genes. Previously described deletions of 12p in acute lymphoblastic leukemias have been recently shown to harbor undetected translocations involving the TEL gene at 12p13. We document a case of an aggressive chronic B-cell leukemia whose cells had trisomy 12 and two unbalanced translocations involving 12p13, including a t(12;22)(p13;q11) as shown by conventional cytogenetics and fluorescence in situ hybridization (FISH). The 12p13 breakpoint of the t(12;22)(p13;q11) was telomeric to the TEL gene, and the second unbalanced translocation with breakpoint 12p13 resulted in the deletion of TEL. This case demonstrates that TEL gene deletions may be relevant in cases of mature B-lymphoproliferative diseases.