Is T-cell CLL a disease entity?
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Chromosome Aberrations↗
Biomedical subjects
V Brito-Babapulle
Publications and source records attributed to V Brito-Babapulle.
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.
Adult↗
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.
Adult↗
Splenic lymphoma with villous lymphocytes: analysis of BCL-1 rearrangements and expression of the cyclin D1 gene.
The translocation t(11;14)(q13;q32) occurs in about 15% of patients with splenic lymphoma with villous lymphocytes (SLVL) or the closely related disorder lymphoplasmacytic lymphoma (LPL). To characterize the nature and frequency of rearrangements of the BCL-1 locus in SLVL/LPL and to document the effect of these genetic alterations on the expression of the cyclin D1 gene, we analyzed 22 cases of SLVL/LPL with defined cytogenetic abnormalities by both conventional electrophoresis (CE) and pulse-field gel electrophoresis (PFGE) and by Northern blotting. Four SLVL/LPL cases showed rearrangement of the BCL-1 locus. In two cases with t(11;14)(q13;q32), different breakpoints were identified; one mapped adjacent to the major translocation cluster (MTC) and the other within a 28-kb region telomeric of it. In a third case of SLVL with no cytogenetic abnormality of 11q13, a novel breakpoint approximately 100 kb centromeric of MTC was detected by PFGE. The fourth case, which had a normal karyotype, demonstrated rearrangement with a BCL-1 probe immediately telomeric of MTC. This case may have had a small deletion of 0.5 kb from within the BCL-1 locus. No rearrangement of the BCL-1 locus or within the cyclin D1 gene was detected by CE or PFGE in any of the remaining 18 SLVL/LPL samples. Northern blot analysis showed expression of a normal-sized cyclin D1 transcript in the two SLVL/LPL cases with t(11;14)(q13;q32). In cases that lacked a cytogenetically demonstrable t(11;14) translocation, no cyclin D1 transcript was detected. Analysis of the BCL-1 locus was also performed in three other cases of B-cell disorders with t(11;14)(q13;q32) detected cytogenetically. Two cases were analyzed by Southern blot and showed rearrangement of the BCL-1 locus. Expression of high-level normal-sized and/or truncated cyclin D1 transcript was also detected in these cases. These data show the importance of PFGE in the detection of rearrangements in the BCL-1 locus and show further the complexity of rearrangements in this locus.
Chromosomes, Human, Pair 11↗
Chromosome abnormalities in hairy cell leukaemia variant.
We describe chromosome abnormalities in 6 patients with hairy cell leukaemia (HCL) variant, a rare B-cell disorder with clinical and laboratory features intermediate between HCL and B-prolymphocytic leukaemia (B-PLL). All but one had marked splenomegaly and a raised white blood cell count (median 40 x 10(9)/l) with over 80% nucleolated hairy cells. These cells had a B-cell immunophenotype distinct from that of typical HCL. All patients but one are alive with stable disease with a median follow-up of 60 months. Numerical chromosome changes included loss of chromosomes 2, 3, 4, 6, 10, 19, 21, and X. three cases had translocations involving the immunoglobulin gene regions: t(14;17)(q32;q11), t(14;22)(q32;q11), and t(2;8)(p11.12;q24). Immunocytochemistry demonstrated the presence of the MYC protein in cells from the case with t(2;8) but not in two others. Other structural abnormalities included t(3;10)(q27;q22) and t(3;12)(q27;q13) in the same patient, der(17)t(7;10;17)(p11;q27;q22), t(1;3)(q25;p21), t(8;21)(p12;q11), t(17;21)(p11;p11), del(6)(q15), del(7)(q34), and del(14)(q24).
Aged↗
Cytogenetic studies in splenic lymphoma with villous lymphocytes.
We report the cytogenetic findings on 31 cases of splenic lymphoma with villous lymphocytes (SLVL). TPA stimulated cells from peripheral blood (28 cases), spleen (two cases) and lymph node (one case) with SLVL have been analysed. A clonal chromosome abnormality was found in 27/31 patients (87%); this was identified as a simple abnormality in 12 cases and a complex one in 15. Four recurring abnormalities were seen: t(11;14)(q13;q32) in five patients, deletions or translocations involving 7q in seven patients, iso 17q in four patients and translocations involving 2p11 in four patients. The high frequency of clonal chromosome abnormalities in SLVL contrasts with the usually benign clinical course of this disease. Abnormalities found frequently in patients with chronic lymphocytic leukaemia (CLL) such as trisomy 12 and deletions or translocations involving 13q14 were each seen in only one patient. No case had the t(14;18) characteristic of follicular lymphoma. Our findings demonstrate the high frequency of clonal and often complex chromosome abnormalities in SLVL. Although a unique chromosome rearrangement has not been identified, a pattern of four recurrent abnormalities has emerged. Our results suggest that SLVL is distinct on cytogenetic grounds from B-CLL and follicular lymphoma but shows similarity with mantle cell lymphoma, lymphoplasmacytic lymphoma and B-PLL.
Adult↗
Translocation t(11;14)(q13;q32) in chronic lymphoid disorders.
The translocation t(11;14)(q13;q32) has been described in a spectrum of B-lymphoproliferative diseases and involves a putative oncogene, BCL1, which maps to chromosome band 11q13. Recent evidence indicates that this abnormality may delineate particular subtypes of lymphoma, such as intermediate lymphocytic and centrocytic lymphomas. Thus the possible significance of the t(11;14) within B-cell disorders should be reexamined in the light of a more objective approach to classifying these diseases by morphology, histology, and immunophenotype. We describe 16 patients with t(11;14)(q13;q32) from a series of 90 patients with chronic lymphoid disorders in whom clonal chromosome abnormalities were detected. All the cases were leukemic: prolymphocytic (B-PLL; 4/15 cases), chronic lymphocytic leukemia (CLL) with increase in prolymphocytes (2/9 cases), or non-Hodgkin lymphoma in leukemic phase, intermediate (3/4 cases), lymphoplasmacytic (2/2 cases), splenic lymphoma with villous lymphocytes (4/18 cases), and follicular (1 case). None of the CLL (25) or hairy cell leukemia cases (15) had t(11;14). Our findings showed that t(11;14) occurred in leukemias of mature B cells with lymphoplasmacytic features as judged by morphology and immunophenotype.
Adult↗
Clinical and laboratory features of 78 cases of T-prolymphocytic leukemia.
We describe the clinical and laboratory findings of 78 adult patients with T-prolymphocytic leukemia (T-PLL) studied over the last 12 years. The main disease features were splenomegaly (73%), lymphadenopathy (53%), hepatomegaly (40%), skin lesions (27%), and a high leukocyte count (greater than 100 x 10(9)/L in 75%) with nucleolated prolymphocytes. A variant form with small, less typical cells was recognized in 19%. Membrane markers defined a postthymic phenotype TdT-, CD2+, CD3+, CD5+, CD7+; in 65%, the cells were CD4+ CD8-, in 21%, they coexpressed CD4 and CD8, and, in 13%, they were CD4- CD8+. Serology for human T-cell leukemia/lymphoma virus Type-I (HTLV-I) was negative in the 27 cases investigated. Cytogenetic analysis in 30 cases showed a consistent abnormality of chromosome 14, usually inv (14), with breakpoints at q11 and q32 in 76% of cases. Trisomy 8, including iso8q, was shown in 53%; t (11;14)(q13;q32) was documented in one case; and one had a normal karyotype. The clinical course was progressive with a median survival of 7.5 months. Thirty-one patients were treated with 2' deoxycoformycin and 15 responded (3 complete remissions and 12 partial remissions); the response rate (48%) increased to 58% in patients with a CD4+ CD8- phenotype. The median survival of responders was 16 months and of nonresponders 10 months; other treatments were less effective. T-PLL is a distinct clinico-pathologic entity with aggressive course and characteristic chromosome abnormalities. A subgroup of patients may benefit from deoxycoformycin.
Adult↗
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.
Ataxia Telangiectasia↗
Leukaemia as a manifestation of large cell lymphoma.
A leukaemic phase is uncommon in large cell lymphoma, particularly at presentation of the disease, and very few cases have been reported since immunological markers became available. We have studied 24 cases presenting over a period of 15 years. 16 were B-lineage and eight T-lineage. In five patients the large cell lymphoma represented a transformation of a preceding low grade, small cell lymphoproliferative disease. Three other patients with T-lineage large cell lymphoma presented with skin infiltration (two cases) or lymphoma-associated nephrotic syndrome (one case) 3-9 months before leukaemia occurred. The other 16 patients (12 B-lineage and four T-lineage) presented with de novo large cell leukaemia/lymphoma. With the exception of skin infiltration, clinical features did not differ between T and B-lineage cases. Prognosis was generally poor although a minority of patients lived 1-2 years. Median survival was 7 months. In the B-cell lymphomas immunological markers were those expected but among the T-cell cases there were many unusual immunophenotypes with frequent failure to express markers which are usually positive in peripheral T cells. Without the availability of immunological markers diagnosis would have been difficult, with acute myeloid leukaemia being the most important differential diagnosis. T-lineage and B-lineage cases could not be distinguished on cytological features. In the majority of cases the cells were very pleomorphic with nuclear lobulation, prominent nucleoli and marked cytoplasmic basophilia being commonly observed. Marked nuclear lobulation was not confined to T-lineage cases but was seen also in seven of 12 cases of de novo B-lineage leukaemia/lymphoma; it was readily apparent in histological sections and on ultrastructural examination.
Adolescent↗
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.
Aged↗
Possible association of disseminated intravascular coagulation (DIC) with the chromosomal region 17q12-21 and the gene for glycoprotein IIb-IIIa complex.
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Chromosome Aberrations↗
The establishment of cell lines from chronic B cell leukaemias: evidence of leukaemic origin by karyotypic abnormalities and Ig gene rearrangement.
We have studied the capacity of peripheral blood cells from 26 chronic B cell leukaemias to proliferate continuously in culture; 72 attempts to establish cell lines were made. The cells were treated in vitro with or without stimulating agents: Epstein-Barr virus (EBV) and/or phorbol-ester (TPA) were the most frequently used. Fourteen cell lines of continuous growth were established from cells from 11 patients, but only four of these were proven to be derived from the original leukaemic cells. Only in the latter four lines were the karyotypic abnormalities and the patterns of immunoglobulin (Ig)-gene rearrangements identical to those found in the patients' leukaemic cells. On the other 10 lines, five had both kappa- and lambda-producing cells, and the remaining five, despite showing light-chain restriction, were proved to be non-leukaemic clones by comparing the Ig-gene rearrangement patterns before and after culture. Three of the four leukaemic cell lines (JVM-2, JVM-3 and JVM-13) were induced by EBV + TPA and derived from prolymphocytic leukaemia (PLL) cases; the fourth (JVM-14) originated from a case of chronic lymphocytic leukaemia (CLL) with increased percentage of prolymphocytes whose cells were stimulated in vitro with EBV. The immunophenotype of the three PLL lines is more mature than that of the original prolymphocytes, as shown by a reduction in surface-Ig and FMC7 expression, enhancement of cytoplasmic-Ig and increase in CD38- and transferrin receptor-positive cells. The cells from line JVM-14 retained the CD5-antigen, a marker of CLL. This study suggests that PLL and some CLL clones are arrested at a stage of maturation ideally suited to be triggered to continuous proliferation in culture. The presence of consistent chromosomal abnormalities in PLL may offer an alternative explanation for the greater proliferative potential of these cells in vitro.
Antigens, Neoplasm↗
T-cell chronic lymphocytic leukaemia: the spectrum of mature T-cell disorders.
Mature (post-thymic) T-cell malignancies comprise a heterogeneous group of diseases with distinct clinical, morphological and immunophenotypic features. As some of these features overlap in the various disorders, it is essential to use a number of diagnostic criteria to define the clinicopathological entities, namely: membrane markers, morphology by light and electron microscopy, clinical features, seroepidemiology of HTLV-I, histopathology, cytogenetic studies and DNA analysis. The latter, which is necessary to document clonality and confirm T-lineage, examines the rearrangement of the T-cell receptor beta, gamma and delta genes. By means of this multiparameter approach, it is possible to distinguish within the post-thymic leukaemias 4 disease entities: T-chronic lymphocytic leukaemia or large granular lymphocyte leukaemia, T-prolymphocytic leukaemia, adult T-cell leukaemia/lymphoma and Sézary syndrome.
Cell Differentiation↗
'Pseudo-lymphoid' leukaemia with unusual features: ultrastructural, immunological, cytogenetic and molecular studies.
An unusual case of 'pseudo-lymphoid' leukaemia is described. The leukaemic cells resembled small, mature lymphocytes but lacked B- and T-cell membrane markers as well as immunoglobulin (Ig) and T-cell receptor gene rearrangements. They showed, instead, features of early myeloid cells since they expressed 2 myeloid antigens, CDW13 and My9, and displayed peroxidase activity demonstrable by electron microscopy (EM) on unfixed cells. Cytogenetic studies showed monosomy 5, t(4;17) (p12;p11), t(2;3)(p23;q14) and an abnormal chromosome 12. Abnormalities of chromosomes 4 and 5 have been previously associated with 'pseudo-lymphoid' leukaemias. This case illustrates the value of sensitive methods for the characterization of blast cells and for the precise diagnosis of leukaemias with apparent 'lymphoid' morphology.
Antibodies, Monoclonal↗
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.
Adult↗
Cytogenetic studies on prolymphocytic leukemia. II. T cell prolymphocytic leukemia.
We report chromosome abnormalities in 15 cases of T cell prolymphocytic leukemia (T-PLL). All cases were characterized by clinical, morphological, and membrane marker analysis. The most frequent abnormality was an inv(14)(q11q32) observed in nine cases. The T cell receptor (TCR) alpha chain gene is localized to 14q11 and the immunoglobulin heavy-chain gene to region 14q32. Four cases also had translocations involving 14q11. Trisomy or multisomy for 8q resulting from an i(8q) or from rearrangements with 8p12 as the breakpoint was observed in nine cases, and a deletion of 6q was found in four cases. Trisomy or partial trisomy for 7q was observed in four cases, of which two had abnormalities of band 7q35 to which the TCR beta chain gene is mapped. The expression of Tac antigen, investigated in 27 cases of human T cell leukemia virus I-negative chronic T cell leukemia, which included the 15 cases of T-PLL, showed a good correlation with abnormalities of 7q35. Our studies on chronic T leukemias suggest that inv(14)(q11q32) and trisomy for 8q are abnormalities characteristic of T-PLL.
Antibody Diversity↗
Cytogenetic studies on prolymphocytic leukemia. 1. B-cell prolymphocytic leukemia.
We describe clonal chromosome abnormalities in 13 new cases of B-cell type prolymphocytic leukemia (B-PLL) investigated using pokeweed, lipopolysaccharide B, TPA (phorbol ester), and Epstein-Barr virus (EBV) as mitogens. B-PLL showed a much better response to all four mitogens when compared with B-cell chronic lymphocytic leukemia (B-CLL). A 14q+ was the most frequent abnormality and was observed in 7 of the 13 cases. A t(11;14)(q13;q32) was observed in 2 patients in this series and in 2 cases from a previous series of 9 patients studied in this laboratory, giving an incidence in B-PLL of 18% for this abnormality. The more frequent rearrangement of both IgH genes in B-PLL when compared to B-CLL may predispose to a higher incidence of 14q+ in B-PLL. Trisomy 12 which is a feature of B-CLL was observed in one case in the present series. Other abnormalities of chromosome 12 included 12p-(p12-13) in 2 cases and t(12;14)(q22;q32) in 1 case. The t(6;12) previously described as a specific abnormality in B-PLL was not observed in the 22 cases (13 present series, 9 previous series) studied in our laboratory.
Aged↗