Heterogeneity of structural abnormalities in the 7q31.3 approximately q34 region in myeloid malignancies

Abnormalities in the long arm of chromosome 7 are a frequent chromosomal aberration in myeloid disorders. Most studies have focused on the analysis of del(7q), demonstrating the presence of several minimal deleted regions in 7q22 approximately q31. By contrast, few studies in myeloid disorders have been devoted to the analysis of translocations, either balanced or unbalanced, involving 7q. In this study, we used fluorescence in situ hybridization (FISH) to characterize the 7q31.3 approximately q34 region (markers D7S480-D7S2227) in patients with deletion or translocation of 7q. A total of 910 cases of myeloid disorders were studied by conventional cytogenetics. Fifty-eight (6%) patients had structural aberrations of 7q. FISH studies were carried out in the 27 patients with involvement of 7q31 approximately q34: 14 cases had an acute myelogenous leukemia and 13 cases had a myelodysplastic syndrome. FISH analysis revealed the existence of high complexity in the 7q31.3 approximately q34 region in patients with unbalanced translocations. No breakpoints in 7q31.3 approximately q34 were found in the cases with deletion or balanced translocation. Nevertheless, studies of unbalanced translocations showed several breakpoints in markers D7S480-D7S2227, which delineate a commonly altered region. The complexity of 7q rearrangements suggests that a synergy of different genetic factors, rather than the alteration of a single tumor suppressor gene, could be involved in the pathogenesis of del(7q) in myeloid disorders.     

A t(1;9)(q23.3 approximately q25;q34) affecting the ABL1 gene in a biphenotypic leukemia

Recurring chromosome translocations, which are found in leukemia, can result in the inappropriate expression of oncogenes or in the formation of chimeric genes that code for structurally and functionally abnormal proteins. The chromosomal t(1;9)(q23.3 approximately q25;q34) was found in a patient with biphenotypic leukemia. Fluorescence in situ hybridization (FISH) analysis revealed that the break on chromosome 9 occurred in the ABL1 gene. The breakpoint on chromosome 1 occurred distal to the PBX1 gene at 1q23.3, as shown by FISH using BAC RP11-503N16 and RP11-403P14, which flank the PBX1 locus; hence, the ABL1 gene can be fused with another gene distal to PBX1 gene.     

Unbalanced translocation der(11)t(11;12)(q23;q13): a new recurrent cytogenetic aberration in myelodysplastic syndrome with a complex karyotype

Cytogenetic abnormalities are observed in approximately one half of cases of myelodysplastic syndrome (MDS). Partial or complete chromosome losses and chromosome gains are frequently found, but there is a relatively high incidence of unbalanced translocations in MDS. We describe here two cases of MDS with an unbalanced translocation, der(11)t(11;12)(q23;q13). Both patients were 69 years of age and diagnosed with refractory anemia with excess of blasts in transformation (RAEB-t) according to the high percentage of blasts in the peripheral blood. Cytoplasmic hypogranulation of neutrophils was evident as a dysplastic change. The blasts were positive for CD4 and CD41a as well as CD13, CD33, CD34 and HLA-DR in both cases. Chromosome analysis showed complex karyotypes including a der(11)t(1;11)(q11;p15)t(11;12)(q23;q13) in case 1 and der(11)t(11;12)(q23;q13) in case 2 plus several marker chromosomes. Spectral karyotyping confirmed the der(11)t(11; 12)(q23;q13) and clarified the origin of marker chromosomes, resulting in del(5q) and del(7q). Fluorescence in situ hybridization (FISH) analyses with a probe for the MLL gene demonstrated that the breakpoints at 11q23 were telomeric to the MLL gene in both cases. FISH also showed that the breakpoint at 11p15 of the case 1 was telomeric to the NUP98 gene. Considering another reported case, our results indicate that the der(11)t(11;12)(q23;q13) is a recurrent cytogenetic abnormality and may be involved in the pathogenesis of advanced-stage MDS.     

Molecular mapping of the chromosome 11 breakpoint of t(11;17)(q13;q21) in a t(11;14)(q13;q32)-positive B non-Hodgkin's lymphoma

The FAU gene is the cellular homologue of the viral FOX sequences in the genome of the Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV); the viral FOX sequences have been shown to increase the transforming capacity of FBR-MuSV in vitro. The human FAU gene has recently been isolated, characterized, and mapped to chromosome band 11q13. Here, we report results of fluorescence in situ hybridization (FISH) analysis which indicate that the FAU gene maps proximally to the putative oncogene BCL1 at 11q13. Furthermore, we identified a t(11;17)(q13;q21) translocation in tumor cells of a t(11;14)(q13;q32)-positive B-cell non-Hodgkin's lymphoma patient by FISH analysis using a FAU containing cosmid clone as molecular probe and by double-colour chromosome painting analysis using chromosome 11- and chromosome 17-specific painting probes. The position of the chromosome 11 breakpoint of the t(11;17) translocation was pinpointed to a human DNA region around the FAU gene of about 40 kbp. © 1993 Wiley-Liss, Inc.     

A der(13)t(7;13)(p13;q14) with monoallelic loss of RB1 and D13S319 in myelodysplastic syndrome

Deletions or translocations of chromosome band 13q14, the locus of the retinoblastoma gene (RB1), have been observed in a variety of hematological malignancies including myelodysplastic syndrome (MDS). We describe here a novel unbalanced translocation der(13)t(7;13)(p13;q14) involving 13q14 in a patient with MDS. A 66-year-old woman was diagnosed as having MDS, refractory anemia with excess of blasts (RAEB-1) because of 7.4% blasts and trilineage dysplasia in the bone marrow cells. G-banding and spectral karyotyping analyses showed complex karyotypes as follows: 46,XX,der(6)t(6;7)(q11;?),der(7)del(7)(?p13)t(6;7)(q?;q11)t(6;13)(q?;q?),der(13)t(7;13)(p13;q14). Fluorescence in situ hybridization (FISH) analyses demonstrated that one allele of the RB1 gene and the microsatellite locus D13S319, located at 13q14 and telomeric to the RB1 gene, was deleted. Considering other reported cases, our results indicate that submicroscopic deletions accompanying 13q14 translocations are recurrent cytogenetic aberrations in MDS. The RB1 gene or another tumor suppressor gene in the vicinity of D13S319, or both, may be involved in the pathogenesis of MDS with 13q14 translocations by monoallelic deletion.     

Translocation t(9;9)(p13;q34) in Philadelphia-negative chronic myeloid leukemia with breakpoint cluster region rearrangement

Chromosome analysis showed a t(9;9)(p13;q34) in a patient with chronic myeloid leukemia (CML) without a Philadelphia (Ph) chromosome in all examined cells. Southern blot analysis of leukocyte DNA revealed rearrangement of breakpoint cluster region (bcr) within the 5.8-kb bcr sequences as in Ph-positive CML patients. The findings confirm that the 9q34 and 22q11 bands are always involved in CML independent of the chromosomal evidence. It is suggested that Ph-negative bcr-positive CML may have variant translocations, as in the case of the t(9;9) reported here.     

New complex chromosomal translocation in chronic myeloid leukaemia: t(9;18;22)(q34;p11;q11)

A Chronic myeloid leukaemia (CML) case with a new complex t(9;18;22)(q34;p11;q11) of a 29-year-old man is being reported. For the first time, this translocation has been characterized by karyotype complemented with fluorescence in situ hybridization (FISH). In CML, the complex and standard translocations have the same prognosis. The patient was treated with standard initial therapy based on hydroxyurea before he died due to heart failure four months later. Our finding indicates the importance of combined cytogenetic analysis for diagnosis and guidance of treatment in clinical diagnosis of CML.     

11q13 is a cytogenetically promiscuous site in hematologic malignancies.

11q13 translocation has been described in mantle cell lymphoma in the form of t(11;14) (q13;q32), with rearrangement and over-expression of the cyclin D1 gene. Recently, an association between 11q13 and acute myeloid leukemia is recognized. We describe the occurrence of 11q13 translocations in both acute leukemias and myelodysplastic syndrome, and suggest that other genetic mechanisms unrelated to cyclin D1 may be involved in the tumorigensis. Furthermore, 11q13 appears to be a cytogenetically promiscuous site involved in reciprocal translocations with different chromosomes in both myeloid and lymphoid malignancies.     

A t(11;12) 11q23 leukemic breakpoint that disrupts the MLL Gene

Translocations involving 11q23 have been shown to be a consistent finding in human hematopoietic malignancies and in some constitutional abnormalities. The identification of a gene, MLL (myeloid/lymphoid or mixed-lineage leukemia), that spans the breakpoints in four different recurrent 11q23 translocations was recently reported. We describe a rare (11;12)(q23;p13) translocation, observed in leukemic cells from a patient with acute lymphoblastic leukemia, which also disrupts this gene. © 1993 Wiley-Liss, Inc.     

Jumping translocation at 11q23 with MLL gene rearrangement and interstitial telomeric sequences

myeloid leukemia of acute myeloid leukemia (AML) M5a showing a jumping translocation with a breakpoint at 11q23. Fluorescence in situ hybridization (FISH) demonstrated triplication of the MLL gene and the presence of interstitial telomeric sequences, supporting the role of repetitive sequences in the mechanism of jumping translocations. Southern blot analysis of the MLL breakpoint cluster region showed the presence of an MLL gene rearrangement. Jumping translocation with MLL gene rearrangement is a previously unreported phenomenon in leukemia cytogenetics.     

Interphase FISH analysis on histologic sections of fixed tissues for t(11;14) (q13;q32) detection in mantle cell lymphoma and t(8;14)(q24;q32) in Burkitt's lymphoma

We describe an interphase FISH analysis for formol-fixed, paraffin-embedded tissue sections with commercial probes detecting the t(11;14)(q13;q32) in mantle cell lymphoma and the t(8;14)(q24;q32) in Burkitt's lymphoma. Staining of an adjacent section allowed identification of tumoral areas. The cut-off value was evaluated in reactive lymph nodes at 5% for both probes. An incomplete hybridization pattern was found in 18 to 26% of the nuclei but was always lower than the percentages of translocated cells in tumoral regions. A t(11;14) was detected in 4/4 mantle cell lymphomas and a t(8;14) in 2/3 Burkitt's lymphomas. Interphase FISH analysis of fixed-tissue sections is a reliable technique for the direct detection of lymphoma-associated translocations on routine histological material.     

Amplification of the 11q23 region in acute myeloid leukemia.

Cytogenetic abnormalities involving the 11q23 region are found in both acute lymphoblastic leukemia (ALL) and myeloid leukemia (AML). Molecular consequences of 11q23 translocations are the formation of chimeric genes, all of them involving the MLL (mixed-lineage leukemia) gene. To evaluate the usefulness of fluorescence in situ hybridization (FISH) in detecting MLL rearrangements in AML, we analyzed 181 patients with an MLL-specific probe. Among them, we detected three patients with multiple FISH signals, reflecting genomic amplification of this chromosomal region. Extra copies of MLL have been reported previously in four patients, but did not correspond to a true gene amplification. For the first time, we describe genomic amplification of the 11q23 region (up to more than 50 copies) in AML patients. This genomic amplification could affect MLL, but other genes in the vicinity could also be the primary target. Genes Chromosomes Cancer 26:166-170, 1999.     

Isodicentric 20q- in two cases of B-cell acute lymphocytic leukemia with the respective t(9;20)(p11;q11.2) and t(9;22)(q34;q11.2)

The cytogenetic anomaly der(20)del(20)(q11.2q13.3)idic(20)(p11), or idic(20q-) in short form, has been reported in 13 cases of myelodysplastic syndrome, one case of chronic myelomonocytic leukemia, and one case of acute myeloid leukemia since 2004. To our knowledge, it has not previously been described in lymphoid diseases. Here we report the cases of two patients with B-cell acute lymphocytic leukemia (ALL) having a novel idic(20q-). One was a 34-year-old man with B-cell ALL whose leukemic cells at presentation had a karyotype of 45,XY,dic(9;20)(p11;q11.2); at relapse, a small marker chromosome was found coexisting with the dic(9;20). The other was a 39-year-old woman with Ph-positive B-cell-ALL whose leukemic cells contained both t(9;22)(q34;q11.2) and a small marker chromosome. A series of FISH analyses using the appropriate probes revealed the small marker chromosome in both patients to be an idic(20q-), confirming the dic(9;20)(p11;q11.2) in one case and revealing a BCR/ABL fusion gene in the other. One patient achieved complete remission but relapsed; the other did not achieve complete remission. Both patients died with a short survival time, despite receiving intensive chemotherapy. These two cases show that idic(20q-) can appear not only in myeloid diseases but also in lymphoid diseases.     

Chromosomal insertion involving MLL in childhood acute myeloblastic leukemia (M4)

Recurrent chromosomal rearrangements involving the 11q23 region have been described in various hematologic malignancies. Among these rearrangements, translocations are the most common mechanism involving the mixed lineage leukemia gene (MLL). Few cases of insertion have been reported and, to our knowledge, none of them involved MLL and chromosome 1. We report a complex karyotype in a childhood acute myelomonocytic leukemia (AML M4) involving the 11q23 region with an insertion between chromosomes 1 and 11 in addition to a translocation between chromosomes 11 and 22. This translocation was clarified by fluorescence in situ hybridization (FISH) analysis: 46,XY,ins(1;11)(q22q23;q13q23),t(11;22)(q13;q11q12). This finding also underlines the complementary contribution of conventional cytogenetic and FISH analysis to detect karyotypic complex abnormalities.