ETS1 gene in myelodysplastic syndrome with chromosome change at 11q23

We examined the c-ets1 gene (located at 11q23) in two myelodysplastic syndrome (MDS) patients displaying a chromosome change at band 11q23 to ascertain any association between this oncogene and the chromosome change. Besides the chromosome change at 11q23, the two MDS patients also showed other numerical and structural changes. Bone marrow cells from the first case showed a translocation between chromosomes 11 and 22, t(?;11;22)(?;p11 or q11----q23;q11), resulting in a Ph-like chromosome. Neither a transposition nor a rearrangement of the c-ets1 gene was detected. Bone marrow cells of the second case showed unidentified chromosomal material attached to bands 11q23 and 6q27. Southern blot study, however, revealed that these cells carried an amplified c-ets1 gene associated with the chromosomal rearrangement. In both MDS cases studied, the amount of c-ets1 related message was the same whether amplification of the c-ets1 gene was present or not, and the level of the c-ets1 gene in MDS cells was very low.     

Overlapping deletion regions at 11q23 in myelodysplastic syndrome and chronic lymphocytic leukemia, characterized by a novel BAC probe set

Translocations or deletions involving the 11q23 region have been observed in acute lymphoblastic leukemia (ALL), acute myelocytic leukemia (AML), myelodysplastic syndrome (MDS), and chronic lymphocytic leukemia (CLL). BAC probes encompassing the D11S29 and D11S924 markers and flanking the MLL gene were used in dual color fluorescence in situ hybridization. Fifteen patients with hematologic malignancies and cytogenetic abnormalities of 11q23 were analyzed. The BAC and MLL probes demonstrated split signals in five of 7 ALL or AML cases with translocations of 11q23. Of the remaining 2 cases, one had normal signals for both probe sets and the other had a submicroscopic deletion of the MLL 3' region. In one case of AML with del(11)(q23), deletion of the MLL 3' region and the region telomeric to the MLL gene was seen. Three CLL cases with deletion of part or the entire 11q23 region showed deletion of one copy of MLL, but retention of the region telomeric to MLL. However, in four MDS cases with deletions involving the 11q23 region, deletions of both the MLL gene and the flanking regions of the MLL gene were observed. Hence, the deletions on 11q23 are different but overlapping for CLL and MDS, implicating different genes involved for these diseases.     

Translocation (11;16)(q23;p13) acute myelogenous leukemia and myelodysplastic syndrome

The purpose of this study is to examine the relationship of t(11;16)(q23;p13) to the type of myeloproliferative disorder noted by hematopathology. Previously, t(11;16) has been reported in fewer than 20 patients, all with the diagnosis of therapy-related (secondary) acute myelogenous leukemia (sAML) or myelodysplastic syndrome (MDS). Putative involved genes are the MLL on 11q23 and CBP at 16p13. Data from The University of Texas M. D. Anderson Cancer Center (UTMDACC) Cytogenetics Laboratory revealed 3 patients with t(11;16) observed during the past 5 years. Two of the patients had a prior diagnosis of non-Hodgkin lymphoma (NHL) and had been treated with chemotherapy, which included cyclophosphamide. The other patient presented with de novo AML and no history of cancer or chemotherapy. Two of the 3 patients had t(11;16) as the sole cytogenetic abnormality. One patient had a t(11;16) clone that included t(9;21) and t(10;21) as additional changes. Translocation (11;16) has previously been reported only as being therapy-related. In this study, the t(11;16) was seen in 2 patients with previous lymphomas treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). A single patient with apparently de novo AML constitutes the first reported instance of non-treatment associated t(11;16) AML.     

11q23 abnormalities in patients with acute myelogenous leukemia and myelodysplastic syndrome as detected by molecular and cytogenetic analyses

11q23 chromosomal abnormalities and rearrangement of the mixed lineage leukemia (MLL) gene are important prognostic factors in acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). However, the presence of 11q23 abnormalities does not always correlate with that of MLL gene rearrangement. We retrospectively compared the occurrence of 11q23 abnormalities (measured by karyotyping) and MLL gene rearrangement (measured by Southern blotting) in bone marrow from 311 consecutive adult patients with AML or MDS. 11q23 abnormalities were found in 18 patients (5.8%), of whom 7 (39%) did not have the MLL gene rearrangement. MLL gene rearrangement was detected in 35 patients (11.2%). Of these 35 patients, only 11 (31%) had cytogenetic evidence of 11q23 abnormalities. None of the 21 patients with chronic myelomonocytic leukemia had 11q23 abnormalities or MLL gene rearrangement. 11q23 abnormalities were associated with shorter survival than was a diploid karyotype. Both cytogenetic and molecular studies should be performed to detect 11q23 abnormalities in patients with AML or MDS.     

Involvement of chromosomes 4, 11, and 17 in a case of myelodysplastic syndrome

A case of myelodysplastic syndrome in a 68-year-old male in whose marrow cells two translocations were established, i.e., t(4;11)(q13;q23) and t(11;17)(p?:q11), as well as other karyotypic changes (?6,?18,15p+), is described. The relation and identity of the bands involved in the translocations affecting chromosomes #11 and #17 in leukemias in which these chromosomes are specifically affected, i.e., t(4;11) in acute myelomonocytic leukemia and t(15;17) in acute promyelocytic leukemia, are discussed in relation to the case described.     

New complex t(2;11;17)(p21;q23;q11), a variant form of t(2;11), associated with del(5)(q23q32) in myelodysplastic syndrome-derived acute myeloblastic leukemia

The t(2;11)(p21;q23) is a rare recurrent aberration observed in myelodysplastic syndrome (MDS) and acute myeloblastic leukemia (AML). It has been suggested that t(2;11) is specifically associated with a deletion of the long arm of chromosome 5 (5q). A 63-year-old man was initially diagnosed as AML with del(5)(q23q32) as a sole abnormality. At relapse, t(2;11;17)(p21;q23;q11) in association with del(5q) appeared in 14 of 20 cells by G-banding. Spectral karyotyping confirmed three derivative chromosomes, der(11)t(2;11), der(17)t(11;17), and der(2)t(2;17). Fluorescence in situ hybridization analysis with a probe for MLL demonstrated that the breakpoint at 11q23 was telomeric to the MLL gene. Nine of 10 reported cases with t(2;11) and del(5q) had MDS including 5q- syndrome and four of them evolved to AML, as observed in the present case. Our results indicated that t(2;11;17) was a secondary genetic change, which appeared during disease progression after del(5q) was observed. Furthermore, considering another reported case, the MLL gene seems to be not involved in the pathogenesis of MDS/AML with t(2;11) and del(5q).     

Identification of a novel fusion gene MLL-MAML2 in secondary acute myelogenous leukemia and myelodysplastic syndrome with inv(11)(q21q23)

We have identified a novel fusion partner of MLL, namely the mastermind like 2 (MAML2 gene), in secondary acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with inv(11)(q21q23). RT-PCR and sequencing revealed that exon 7 of MLL was fused to exon 2 of MAML2 in the AML and MDS cells. The inv(11)(q21q23) results in the creation of a chimeric RNA encoding a putative fusion protein containing 1,408 amino acids from the NH2-terminal part of MLL and 952 amino acids from the COOH-terminal part of MAML2. The NH2-terminal part of MAML2, a basic domain including a binding site of the intracellular domain of NOTCH, was deleted in MLL-MAML2. MLL-MAML2 in secondary AML/MDS and MECT1-MAML2 in mucoepithelioid carcinoma, benign Wartin's tumor, and clear cell hidradenoma consist of the same COOH-terminal part of MAML2. A luciferase assay revealed that MLL-MAML2 suppressed HES1 promoter activation by the NOTCH1 intracellular domain. MAML2 involving a chimeric gene might contribute to carcinogenesis in multiple neoplasms by the disruption of NOTCH signaling.     

Cytogenetic findings in siblings with a myelodysplastic syndrome

A brother and sister, both in their third decade, presented 6 months apart with severe pancytopenia. Bone marrow examination demonstrated morphologic changes, characteristic of the myelodysplastic syndromes, subtype refractory anemia with excess of blasts; cytogenetic studies revealed complex but different karyotypic abnormalities in both siblings. No history of exposure to mutagenic agents was obtained; there was no evidence of congenital anomalies in the family. Both siblings died within 18 months of diagnosis from complications related to their disease. This report describes the clinical course and discusses the cytogenetic findings for both siblings.     

Central nervous system abnormalities in chromosome deletion at 11q23

Two Japanese pediatric patients with terminal deletion of the long arm of chromosome 11 are described. Both had the morphological abnormalities of the 11q deletion syndrome, such as prominent epicanthal folds, broad flat nasal bridge with short, upturned nose, short philtrum with carp-shaped mouth, cardiac anomalies and nonprogressive moderate psychomotor developmental delay. Patient 1 is the first case to be reported with 11q deletion with serial magnetic resonance (MR) examinations of cerebral white matter. The initial MR imaging studies demonstrated multiple areas of T1 and T2 prolongation in the cerebral white matter in both patients at the ages of 2 5/12 and 2 1/12 years, respectively. A second MR imaging, performed 1 year after the first in Patient 1, demonstrated slight improvement of the lesions. Neither patient showed clinical deterioration. These results suggest that the lesions were caused by delayed myelination, rather than by demyelination. It is suggested that an unknown factor which is important for myelination is located on the long arm of chromosome 11: perhaps the neural cell adhesion molecule (NCAM).     

Jacobsen distal 11q deletion syndrome with a myelodysplastic change of hemopoietic cells

We describe a male infant with unusual facial appearance, relative pancytopenia, bilateral simian creases, and an accessory nipple. Cytogenetic analysis showed deletion of the long arm of chromosome 11 [46,XY,del(11)(pter→q23.2:)]. Bone-marrow study showed a myelodysplastic change of hemopoietic cells compatible with peripheral blood findings. Pachygyria of the temporal and frontal lobes was demonstrated by magnetic resonance image (MRI) of the brain. We present our findings in order to contribute to the information on 11q23 deletion. Am. J. Med. Genet. 75:341-344, 1998. © 1998 Wiley-Liss, Inc.     

Cytogenetic t(11;17)(q13;q21) in a pediatric ependymoma. Is 11q13 a recurring breakpoint in ependymomas?

Cytogenetic studies on a supratentorial ependymoma from a 1-year-old boy showed a t(11;17)(q13;q21). This is the second ependymoma reported with a rearrangement at 11q13; to our knowledge the 11q13 is the first recurring breakpoint reported in ependymoma.     

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.     

Cytogenetic analysis of 54 cases of myelodysplastic syndrome

Fifty-four patients with myelodysplastic syndrome (MDS) (35 men and 19 women aged 34-92 years) were studied cytogenetically. Bone marrow cell culture and chromosome preparation were performed according to four different protocols used in parallel: methotrexate (MTX)-synchronized or thymidine (TdR)-unsynchronized techniques, and presence or absence of 5637 conditioned medium (CM). Some patients responded better to MTX; others had better results with TdR exposure only. Use of 5637 CM generally improved quantity and quality of metaphases. A cytogenetic result was obtained in 53 cases. 60% of the patients had a chromosome abnormality. Percentage of abnormality varied from one French-American-British (FAB) subtype to the other: 62% in refractory anemia with ringed sideroblasts (RARS, 8/13), 50% in refractory anemia (RA, 6/12), 60% in refractory anemia with excess of blasts (RAEB, 3/5), 77% in refractory anemia with excess of blasts in transformation (RAEB-T, 7/9), and 57% in chronic myelomonocytic leukemia (CMMoL, 8/14). Chromosome defects were subdivided into three categories: single, two, and complex defects. The most frequent chromosome abnormalities, either single or one of two or complex defects were del(5q) or monosomy 5 (13 cases), trisomy or rearrangement of chromosome 8 (eight cases), total or partial monosomy or rearrangement of chromosome 7 (eight cases), Y loss (seven cases), and del(20q) (two cases). With the exception of del(5q) in macrocytic RA, this study confirms the absence of chromosome defects specific to each FAB category of MDS. Recurrent defects in MDS are relatively limited, however, in terms of chromosomes involved and type of abnormality. Consequently, these defects, mostly of deleted type, are assumed to play a specific role in the genesis of myelodysplasia.     

11q23 balanced chromosome aberrations in treatment-related myelodysplastic syndromes and acute leukemia: report from an international workshop

Among 511 patients with therapy-related myelodysplastic syndrome or acute leukemia (t-MDS/t-AL) and balanced chromosome aberrations, 162 (32%) had translocations involving 11q23. The recurring translocation partners were 9p22 (48%), 19p13.3 (11%), 19p13.1 (10%), 4q21 (9%), 6q27 (6%), 1p32 (2%), 16p13.1 (2%), 10p13 (1%), and 17q25 (1%); in 9%, the translocations were seen only once. The remaining 349 patients were divided into five subgroups based on the balanced aberration: 21q22, inv(16), t(15;17), Rare, and Unique aberrations. Patients in the 11q23 subgroup had a sole cytogenetic abnormality more often than those in the 21q22, inv(16), Rare, and Unique subgroups, and a complex karyotype or -5/del(5q) and/or -7/del(7q) less often than patients in the 21q22, Rare, and Unique subgroups. Clinically, 11q23 patients had acute lymphoblastic leukemia (ALL) more often as their primary disease and a shorter latency from start of treatment for the primary disease to their t-MDS/t-AL diagnosis, except when compared with the inv(16) subgroup. The 11q23 subgroup demonstrated a younger age at t-MDS/t-AL diagnosis, but this finding was not significant when patients with AL as their primary diagnosis were excluded. Survival from the time of diagnosis of t-MDS/t-AL was significantly shorter for the 11q23 subgroup compared with that of the 21q22, inv(16), and t(15;17) subgroups (median 8 vs. 14, 28, and 29 months, respectively). Inferior survival occurred even though 11q23 patients were younger and more often received blood or marrow transplantation (BMT). Even among patients receiving BMT, 11q23 patients had a shorter median survival (9 vs. 12-31 months for the other subgroups). However, among 11q23 patients, those receiving BMT survived longer, with 1- and 5-year survivals of 43% and 18% compared with 23% and 7% for patients not transplanted. With regard to prior therapy, 11q23 patients, compared with other patients, received radiotherapy less often as their sole therapy and chemotherapy more often. They had received VP16, methotrexate, 6MP/6TG, L-asparaginase, daunorubicin, cytarabine, and VM26 more often, likely attributed to the high frequency of AL as their primary disease. More patients in the 11q23 subgroup had received doxorubicin, except in comparison with the 21q22 subgroup; more vincristine, except in comparison with the Rare and Unique subgroups; and more prednisone, except in comparison with the Unique subgroup. Patients in the 11q23 subgroup more often received alkylating agents (AAs) (86% vs. 59-82% for the other subgroups), and topoisomerase II inhibitors (TIs) (84% vs. 49-75%), and they more often reported exposure to AAs plus TIs without radiotherapy (33% vs. 12-21%), except in comparison with the 21q22 subgroup (36%). We performed a multivariate analysis to determine whether the adverse survival of 11q23 patients compared to other Workshop patients was explained by factors other than the presence of the 11q23 abnormality. Covariates in the final model were the five cytogenetic subgroup indicators, where the 11q23 subgroup was the referent (P < 0.0001); age at t-MDS/t-AL (P = 0.0036); previous exposure to lomustine (P < 0.0001) and mitoxantrone (P = 0.0225); BMT for t-MDS/t-AL (P = 0.0006); and karyotype complexity (P = 0.0114). The risk of death for 11q23 patients relative to patients in the 21q22, inv(16), t(15;17), and Unique subgroups was significant, even after adjustment for other risk factors (relative risks 2.3, 3.6, 3.1, and 1.5, respectively; P < 0.0001 for the first three comparisons and P = 0.0125 for the last). When a multivariable model was constructed, excluding patients with AL or MDS as their primary diagnosis, the relative risk of death for 11q23 patients was significantly higher than that of all five other cytogenetic subgroups. We conclude that among t-MDS/t-AL patients with balanced aberrations, 11q23 translocations are an independent adverse risk factor. Although BMT is the current therapy of choice, new treatment is required.     

Frequent amplification of 8q24, 11q, 17q,and 20q-specific genes in pancreatic cancer

Genetic changes involved in the development and progression of pancreatic cancer are still partly unknown, despite the progress in recent years. In this study, comparative genomic hybridization analysis in 31 pancreatic cancer cell lines showed that chromosome arms 8q, 11q, 17q, and 20q are frequently gained in this tumor type. Copy number analysis of selected genes from these chromosome arms by fluorescence in situ hybridization showed amplification of the MYC oncogene in 54% of the cell lines, whereas CCND1 was amplified in 28%. In the 17q arm, the ERBB2 oncogene was amplified in 20% of the cell lines, TBX2 in 50%, and BIRC5 in 58%, indicating increased involvement toward the q telomere of chromosome 17. In the 20q arm, the amplification frequencies varied from 32% to 83%, with the CTSZ gene at 20q13 being most frequently affected. These results illustrate that amplification of genes from the 8q, 11q, 17q, and 20q chromosome arms is common in pancreatic cancer.