7q32-q36 translocations in childhood T cell leukemia: cytogenetic evidence for involvement of the T cell receptor beta-chain gene

Blast cell chromosomal rearrangements involving the long arm of chromosome 7 were identified in eight of 197 cases of childhood acute lymphoblastic leukemia (ALL). Breakpoints were variable but tended to cluster in either the proximal or the terminal 7q region, depending on the immunophenotype of the cells. The 7q32-q36 region, the locus of the T cell receptor beta-chain gene, was the site of breakpoints in four of 31 cases of T cell ALL but was not involved in any of the 166 cases originating from B cell precursors (P less than .0004). In three of the four T cell cases it was possible to identify the chromosomal segment that had been translocated to the 7q32-q36 region: 1p32, 2p21, and 6p21. The 1p32 and 6p21 bands are particularly interesting, as they contain the sites of two known protooncogenes, c-L-myc and hpim, respectively. Our findings suggest that the locus of the beta-chain gene of the T cell receptor is a preferential site for certain chromosomal rearrangements in leukemic T lymphoblasts, analogous to the T cell receptor alpha-chain gene on human chromosome 14. Translocation of proto-oncogenes to a site near the beta-chain regulatory sequences provides a potential mechanism for oncogene activation.     

Molecular characterization of the 7q deletion in myeloid disorders

Deletion of the long arm of chromosome 7 is a common karyotypic finding in myeloid disorders and in particular is found in association with secondary leukaemias. We have used restriction fragment length polymorphisms and gene dosage experiments to assess the loss or retention of sequences localized to chromosome 7q in five patients with clonal myeloid disorders and a 7q deletion. The deletion was interstitial in all cases with retention of the anonymous marker pS194 located at 7q36-qter. Three out of five cases also retained the more proximal gene T-cell receptor β (TCRβ) located at 7q35. The proximal breakpoints of all five cases were localized to 7q22 by cytogenetic analysis. In two cases the proximal breakpoint lay between the genes for elastin (ELN) and collagen type 1α (COL1A2) and in three cases distal to this region between the genes for erythropoietin (EPO) and acetylcholinesterase (ACHE). The genes for ACHE, plasminogen activator inhibitor 1 (PLANH1), CCAAT displacement protein (CUTL1) and Met proto-oncogene (MET) were deleted in all cases. Molecular analysis of the 7q deletion in myeloid leukaemias demonstrates heterogeneity of the breakpoints, supporting a recessive mechanism of tumourigenesis.     

Molecular definition of a narrow interval at 7q22.1 associated with myelodysplasia

Chromosome 7 translocations, deletions, or monosomy are associated with myelodysplasia (MDS) and acute myeloid leukemia both in children and adults. These chromosomal anomalies represent one of the most common cytogenetic abnormalities associated with these diseases and usually herald a poor prognosis. In this study two cosmid DNA probes that mapped to 7q22.1 and were known to be separated by approximately 500 kb were identified to flank the proximal inversion breakpoint in a patient carrying a constitutional inversion (7q22.1-34) associated with MDS. A yeast artificial chromosome (YAC) clone that encompassed the two cosmids was identified and shown to span the breakpoint. Fluorescence in situ hybridization was then used to analyze six additional patients with myelodysplasia and chromosomal rearrangements of the 7q22 region (three patients had translocations and three carried deletions). The breakpoint in one of the patients was found to be contained within the same YAC clone that spanned the inversion breakpoint. Moreover, this same interval was determined to be absent in all three patients with chromosomal deletions. These results suggest that this segment of DNA on chromosome 7q22.1 may contain specific gene(s) that have a significant role in myeloid malignancies.     

Dup(12)(q13-q22) and 13q14 deletion in a case of B-cell chronic lymphocytic leukemia

Cases with partial trisomy 12 have rarely been found in B-cell chronic lymphocytic leukemia (CLL). We report our clinical, cytogenetic and fluorescence in situ hybridization (FISH) findings in a CLL patient with a duplication of part of the long arm of chromosome 12 between bands q13-q22. This patient was the only case with this duplication among the 112 cases (0.9%) of CLL cytogenetically analyzed in our laboratory. FISH studies using unique-sequence specific probes for the RB-1 (retinoblastoma) gene and the D13S319 locus at the 13q14 band showed a monoallelic loss for the D13S319 locus (20% of cells) with a diploid RB-1 gene. Our case showed an atypical morphology (35% prolymphocytes), a high proliferation rate and progression of the disease, indicating that the duplication of this region may be equivalent to complete trisomy 12 in CLL patients.     

Performance of Sokal and Eutos Scores for Predicting Cytogenetic and Molecular Response in Newly Diagnosed Chronic Myeloid Leukemia-Chronic Phase Patients on Imatinib

Sokal index was developed in the pre-imatinib era to predict and prognosticate the outcome of Chronic myeloid leukemia (CML) patients. In the Imatinib era, a new scoring system called EUTOS scoring system has been validated as a predictive marker in CML. The scores have shown variable correlation with complete cytogenetic response (CCyR) and major molecular response (MMR). To assess the performance of Sokal score and EUTOS score as a predictive marker for CCyR and MMR for newly diagnosed CML-CP patients treated with TKIs. 273 patients with newly diagnosed CML were included in the study. They were treated with upfront imatinib. They were followed up for a median period of 3 years. Cytogenetic and Molecular response to the treatment were monitored regularly. Out of 273 patients, 174 patients (63 %) were having low EUTOS score and 99 (37 %) were having high EUTOS score. Patients with low, intermediate and high sokal scores were 237 (86.8 %), 28 (10.3 %) and 8 (2.9 %) respectively. 122 patients with low EUTOS score achieved CCyR within 18 months compared to 42 patients with high EUTOS score (p = 0.000).113 patients with low EUTOS score achieved MMR in 18 months compared to 33 patients with high EUTOS score (p = 0.000). 148, 14, 2 patients with low, intermediate and high Sokal score respectively have achieved CCyR in 18 months (p = 0.054). 133, 11, 2 patients with low intermediate and high sokal score respectively have achieved MMR in 18 months.(p = 0.06). EUTOS is better than Sokal score in predicting the outcome of patients of CML treated with imatinib.     

Cytogenetic Differences between Bone Marrow and Spleen in a Case of Agnogenic Myeloid Metaplasia Developing Blast Crisis

Chromosome studies of cells from bone marrow and spleen were performed in a patient with agnogenic myeloid metaplasia (MM) developing blast crisis after a chronic phase lasting for 6.5 years. The proportions of blast cells were roughly the same in bone marrow and spleen. In the bone marrow 43% of the metaphases were abnormal with a marker chromosome whereas all spleen metaphases were normal. The results indicate that chromosomal changes associated with blast transformation in MM may occur in the bone marrow prior to such changes in the spleen and support the concept that bone marrow and spleen may constitute relatively separate pools of haemopoietic tissue in chronic myeloproliferative diseases.     

Abnormalities of 3q21 and 3q26 in myeloid malignancy: a United Kingdom Cancer Cytogenetic Group study

Summary. Cytogenetic and clinical details are presented for 66 patients with myeloid malignancy and chromosome abnormalities of 3q21 and/or 3q26 (3qabns). Bone marrow and/or peripheral blood morphology was assessed for 52 cases. 3qabns in Philadelphia negative (Ph–ve) and positive (Ph + ve) cases were inv(3)(q21q26), (21 Ph-ve, 6Ph + ve); t(3;3)(q21;q26) (nine Ph-ve, four Ph + ve); and t(3;21)(q26;q22) (four Ph-ve, six Ph + ve). Ph-ve cases also had t(l;3)(p36;q21) (three cases), and t(3;5)(q21;q31)/ (q21;q35)/(q26;q21) (five cases aged <40 years). Three cases, aged < 30 years, had t(3;12)(q26;p13) which defines a new 3qabn subgroup. Monosomy 7 and/or 5q- accompanied inv(3) or t(3;3) in 17/30 cases. All cases had a myeloid malignancy (predominantly AML M1, M4 or M7), frequent trilineage myelodysplasia, and markedly abnormal megakaryopoiesis with micromegakaryocytes (<30/mi). Thrombocytosis occurred in two cases only. Most Ph + ve cases were in myeloid blast crisis and in Ph + ve cases alone, micro-megakaryocytes were uniquely small (10 μm) in 7/11 cases. There were equal numbers of males and females. Seven secondary leukaemias were found in Ph–ve cases with inv(3), t(3;3), t(3;21), t(l;3) or del(3)(q21). Three cases with t(3;21) (one Ph + ve) were de novo AML or had de novo aplastic anaemia. Survival was rarely greater than 12 months from detection of the 3qabn.     

Cytogenetic profile of acute lymphocytic leukemia patients: report of a novel translocation t(4;13) (q21 x 3; q35) from an Indian population

Acute lymphocytic leukemia (ALL) is a malignant neoplasm characterized by clonal proliferation, decreased apoptosis and accumulation of immature lymphoid cells in the bone marrow as well as the peripheral blood. The aim of this study was to determine the overall cytogenetic profile of Indian ALL patients along with their frequency and distribution pattern. A total of 75 ALL subjects were included in the study. The major outcome of the work was identification of a novel translocation t(4;13) (q21 x 3;q35) that has not yet been reported. In addition, a few rare chromosomal aberrations such as t(4;16) (p16;q12 x 2) and t(7;10)(q36;q21 x 2) were also detected. Overall, of 75 cases, 67 (89 x 33%) were successfully karyotyped. Normal and abnormal karyotypes were seen in 38 (56 x 7%) and 29 (43 x 3%) cases respectively. Various other abnormalities were hyperdiploidy (20 x 68%), hypodiploidy (10 x 34%), t(8;14) (3 x 44%), t(9;22) (6 x 9%), t(4;16) (3 x 44%), t(7;10) (3 x 44%) and gain of chromosome 8, 13, 16, and 22 was seen in one case each (3 x 44%). Deletions in chromosome 5, 9 and 11 were found to be 3 x 44, 6 x 89 and 6 x 89% respectively, while complex and other aberrations were detected in 3 x 44 and 13 x 8% cases. Finally, we conclude that cytogenetic analysis has an important role in routine genetic diagnostic workup and management of ALL patients.     

Evaluation of Long-Term Outcomes, Cytogenetic and Molecular Responses with Imatinib Mesylate in Early and Late Chronic-Phase Chronic Myeloid Leukemia: A Report from a Single Institute

Here we compare the management and survival outcomes of chronic myeloid leukemia (CML) patients who had early or late imatinib mesylate (IM) therapy. The cytogenetic and molecular responses of 189 CML patients were analyzed. Of this group, 121 patients were classified as the early chronic phase (ECP) group and started IM within 12 months of diagnosis. The other 68 patients were classified as the late chronic phase (LCP) group who had been treated with interferon (IFN)-alpha-2 and crossed over to IM more than 12 months after diagnosis. The overall rates of complete cytogenetic response (CCyR) and major molecular response (MMR) at last follow-up were 83.6 and 78.1% in the ECP and LCP groups, respectively. The CCyR rates were 89.3 (for ECP patients) versus 73.5% (for LCP patients; p < 0.0001). At last follow-up, 82.4% ECP and 64.2% LCP patients had achieved an MMR (p < 0.0001). No significant differences were noted between the two groups with regard to survival outcomes. Our experience reveals that IM is an effective rescue therapy in most CML LCP patients who are intolerant or in whom IFN-alpha therapy fails. Such therapeutic options should be considered in LCP patients, particularly in countries where IM may not be available.     

Malignant histiocytosis: a specific t(2;5)(p23;q35) translocation? Review of the literature

In this paper, the investigators report a well documented case of malignant histiocytosis (MH) with a t(2;5)(p23;q35) translocation. A breakpoint in 5q35 appears to be specific, either for the disease or for a subclass of the disease. Additional cases of MH with cytogenetics are needed. This will help to determine if one class of MH or several subclasses can be defined by cytogenetic anomaly(ies).     

Human insulin receptor substrate-1 gene (IRS1): chromosomal localization to 2q35-q36.1 and identification of a simple tandem repeat DNA polymorphism

Summary The protein designated as insulin receptor substrate-1 (IRS-1) is a major substrate for the insulin receptor tyrosine kinase. Since post-receptor defects in the insulin signalling pathway are a common feature of Type 2 (non-insulin-dependent) diabetes mellitus, we have cloned the human IRS-1 gene in order to study the role of genetic variation in this gene in the pathogenesis of diabetes mellitus. As a first step in these studies, we have mapped the IRS-1 gene to chromosome 2, bands q35–q36.1 and identified a simple tandem repeat DNA polymorphism in this gene that will be useful for genetic studies.     

Cytogenetic and molecular delineation of a region of chromosome 3q commonly gained in marginal zone B-cell lymphoma

BACKGROUND AND OBJECTIVES: Whole or partial trisomy 3 represents the most recurrent chromosomal abnormality occurring in marginal zone B-cell lymphoma (MZBCL), a distinct subtype of B-cell non-Hodgkin's lymphoma (NHL). By conventional cytogenetic analysis, unbalanced translocations involving chromosome 3 and leading to a partial trisomy 3q were identified in a series of 14 MZBCL patients. Fluorescent in situ hybridization (FISH) experiments were then performed to characterize the breakpoints further and to delineate the extent of the 3q gained region more accurately. DESIGN AND METHODS: We studied 14 cases of MZBCL combining cytogenetics and FISH techniques using specific probes for the long arm of chromosome 3, including the chromosome 3 a satellite probe, a representative panel of yeast artificial chromosome (YAC) clones mapping the chromosomal 3q region (3q11.2 to 3q23) and the chromosome 3 subtelomeric (3q29) probe. RESULTS: In the 14 cases, additional chromosome 3q material was found to be involved in different unbalanced translocations with chromosomes 1, 6, 7, 8, 11, 13, 14, 15, 17, 19 and 21, leading to a derivative chromosome. None of the chromosomal abnormality juxtaposed the 3q regions with the heavy and/or light k and l immunoglobulin gene loci. Eight different breakpoints distributed between the 3q11.2 and the 3q13.32 regions were identified and a common 3q13.32 3q29 overrepresented region was delineated. INTERPRETATION AND CONCLUSIONS: These results suggest that this critical region may be of importance in the pathogenesis of MZBCL and support the hypothesis that a gene dosage effect rather than a specific gene disruption may be involved in the development of this disease.     

Identification of a novel chromosome region, 13q21.33-q22.2, for susceptibility genes in familial chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is the most prevalent form of leukemia in adults in western countries. A genome scan of CLL-prone families revealed a lod score of one in band 13q22.1. To investigate this finding, we selected 6 CLL families consisting of 63 individuals (CLL affected, n=19; unaffected, n=44) for fine mapping of a 23-megabase region in 13q14.2-q22.2. Interphase fluorescence in situ hybridization (FISH) revealed 13q14 deletion in 85% (11/13) of CLL patients. Four CLL families shared a 3.68-Mb minimal region in 13q21.33-q22.2. Two asymptomatic siblings who shared the 13q21.33-q22.2 at-risk haplotype exhibited CD5+ monoclonal B-cell lymphocytosis (MBL) on flow cytometry. One of these individuals also had a 13q14 deletion by FISH. These 2 individuals with MBL shared the at-risk haplotype with their CLL-affected relatives, providing further evidence of the relationship between CLL and MBL, as well as of the biologic significance of this novel region. Using direct DNA sequencing analysis, we screened 13 genes for mutations, but no frameshift or nonsense mutations were detected. Our studies revealed that 11 of the 13 genes in the candidate region were expressed in immune tissues, supporting their functional relevance in investigations of familial CLL. In conclusion, we identified a novel candidate region that may predispose to familial CLL.