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Inv(3)(q21q26)/t(3;3)(q21;q26) is recognized as a distinctive entity of acute myeloid leukemia (AML) with recurrent genetic abnormalities of prognostic significance. It occurs in 1-2.5% of AML and is also observed in myelodysplastic syndromes and in the blastic phase of chronic myeloid leukemia. The molecular consequence of the inv(3)/t(3;3) rearrangements is the juxtaposition of the ribophorin I (RPN1) gene (located in band 3q21) with the ecotropic viral integration site 1 (EVI1) gene (located in band 3q26.2). Following conventional cytogenetics to determine the karyotype, fluorescent in situ hybridization (FISH) with a panel of bacterial artificial chromosome clones was used to map the breakpoints involved in 15 inv(3)/t(3;3). Inv(3) or t(3;3) was the sole karyotypic anomaly in 6 patients, while additional abnormalities were identified in the remaining 9 patients, including 4 with monosomy of chromosome7 (-7) or a deletion of its long arm (7q-). Breakpoints in band 3q21 were distributed in a 235 kb region centromeric to and including the RPN1 locus, while those in band 3q26.2 were scattered in a 900 kb region located on each side of and including the EVI1 locus. In contrast to most of the inversions and translocations associated with AML that lead to fusion genes, inv(3)/t(3;3) does not generate a chimeric gene, but rather induces gene overexpression. The wide dispersion of the breakpoints in bands 3q21 and 3q26 and the heterogeneity of the genomic consequences could explain why the mechanisms leading to leukemogenesis are still poorly understood. Therefore, it is important to further characterize these chromosomal abnormalities by FISH.

Chromosomal analysis was successfully performed in 34 of the 37 patients with T-cell acute lymphoblastic leukemia (ALL) seen at the University Hospital in Brest (France) between 1981 and 2002. A normal karyotype was observed in 29.4% of the patients. Numerical changes were rare, 79.2% of the abnormal karyotypes being pseudodiploid. All 24 abnormal karyotypes had at least a structural rearrangement. Translocations involving band 14q11, that contains the T-cell receptor (TCR) alpha and delta-genes, were observed in 8 patients; in 3 of them, a new partner chromosomal band was found. The short arms of chromosomes 11 and 12 were involved in 3 and 2 translocations respectively. Three patients had a del(6q). Our results are in agreement with those of the literature. Most of the recurrent abnormalities are different from those of B-lineage ALL. Some are known to involve TCR genes whereas others can lead to the discovery of new genes that are important to T-lineage leukemogenesis.

Abstract: Chromosomal rearrangements involving the MLL gene have been associated with many different types of hematological malignancies. Fluorescent in situ hybridization with a panel of probes coupled with long distance inverse-PCR was used to identify chromosomal rearrangements involving the MLL gene. Between 1995 and 2010, 27 patients with an acute leukemia were found to have a fusion gene involving MLL. All seven ALL patients with B cell acute lymphoblastic leukemia were characterized by the MLL/AFF1 fusion gene resulting from a translocation (5 patients) or an insertion (2 patients). In the 19 AML patients with acute myeloblastic leukemia, 31.6% of all characterized MLL fusion genes were MLL/MLLT3, 21.1% MLL/ELL, 10.5% MLL/MLLT6 and 10.5% MLL/EPS15. Two patients had rare or undescribed fusion genes, MLL/KIAA0284 and MLL/FLNA. Seven patients (26%) had a complex chromosomal rearrangement (three-way translocations, insertions, deletions) involving the MLL gene. Splicing fusion genes were found in three patients, leading to a MLL/EPS15 fusion in two and a MLL/ELL fusion in a third patient. This study showed that fusion involving the MLL gene can be generated through various chromosomal rearrangements such as translocations, insertions and deletions, some being complex or cryptic. A systematic approach should be used in all cases of acute leukemia starting with FISH analyses using a commercially available MLL split signal probe. Then, the analysis has to be completed, if necessary, by further molecular cytogenetic and genomic PCR methods. [Copyright &y& Elsevier]

Abstract: Band 11q23 is known to be involved in translocations and insertions with a variety of partner chromosomes. They lead to MLL rearrangement, resulting in a fusion with numerous genes. We report here 2 male adults in whom a diagnosis of acute myelomonoblastic leukemia (FAB M4) and acute monoblastic leukemia (FAB M5) was made. Conventional cytogenetic techniques showed a 45,XY,t(1;11)(p32;q23),-7 karyotype in the first case and a 46,XY, t(11;17)(q23;q21) in the second case. Fluorescent in situ hybridization (FISH) with a specific MLL probe showed the gene to be disrupted, the 3′ region being translocated on the derivative chromosomes 1 and 17, respectively. Fourteen and 24 patients, including ours, with acute myeloblastic leukemia associated with a t(1;11)(p32;q23) and a t(11;17)(q23;q21), respectively have been reported in the literature. Several patients with the latter translocation have also been identified to have acute lymphoblastic leukemia (ALL). Although both translocations are preferentially associated with monocytic differentiation, the t(11;17)(q23;q21) is more common in adults and has been reported in many patients with ALL, compared to the t(1;11)(p32;q23). [Copyright &y& Elsevier]

Band 11q23 is known to be involved in translocations and insertions with a variety of partner chromosomes. In most cases, they lead to MLL rearrangements, resulting in a fusion with numerous genes. We report here a newborn girl who had disseminated intravascular coagulation and cutaneous tumors (granulocytic sarcomata) in whom a diagnosis of acute myeloblastic leukemia (AML) FAB-M5 was made. Conventional cytogenetics using R-banding showed 11 of the 17 metaphases observed to have a 46,XX,t(1;11)(p36.2;q23) karyotype. FISH analysis confirmed the disruption of the MLL gene. Two adult patients solely have been found to have a t(1;11)(p36;q23); however, no FISH analysis with a MLL probe was performed in both cases. Since the diagnosis was made at birth, this implies that the MLL rearrangement and the onset of the disease occurred in utero . Twenty children, including 3 newborns, have been reported to have granulocytic sarcoma associated with 11q23/ MLL rearrangement. To the best of our knowledge, this is the first report of a case of congenital AML with GS arising in a patient with proven MLL rearrangement. [ABSTRACT FROM AUTHOR]

We report a 2-year-old boy with B-cell acute lymphoblastic leukemia. Cytogenetic studies at diagnosis with R-banding showed a 46,XY,ins(12;3)(p13;q?21q?22)/46,XY karyotype. Fluorescence in situ hybridization with TEL/AML1 probes and chromosome paints revealed complex rearrangements. The TEL/AML1 fusion gene was located on the derivative chromosome 21 but a segment of the long arm of a chromosome 3 was inserted between the proximal part of the short arm of the derivative chromosome 12 and the reciprocal part of the AML1 gene. This is consistent with an insertion of chromosome 3 into chromosome 12 after the t(12;21) took place, therefore indicating a probable secondary event due to clonal evolution. [Copyright &y& Elsevier]

Simple Summary: The world population is genetically and environmentally diverse. In particular, genetic differences related to an ethnic factor may underlie differences in cancer phenotypic expression. Therefore, we compared the epidemiology, and the clinical, biological and genetic characteristics of myelodysplastic syndrome (MDS) between Asian and Western countries. Our results show substantial differences in the incidence and age of onset between Asian and Western MDS patients. A higher proportion of Asian MDS patients fall into the high- and very-high risk prognostic MDS groups. This finding is supported by the identification of a higher proportion of high-risk cytogenetic aberrations in Asian MDS patients. However, the survival rate is similar for Western and Asian MDS patients. Our findings may impact the clinical management as well as the strategy of clinical trials targeting those genetic aberrations and mutations depending on the world area where they are run. This study explores the hypothesis that genetic differences related to an ethnic factor may underlie differences in phenotypic expression of myelodysplastic syndrome (MDS). First, to identify clear ethnic differences, we systematically compared the epidemiology, and the clinical, biological and genetic characteristics of MDS between Asian and Western countries over the last 20 years. Asian MDS cases show a 2- to 4-fold lower incidence and a 10-year younger age of onset compared to the Western cases. A higher proportion of Western MDS patients fall into the very low- and low-risk categories while the intermediate, high and very high-risk groups are more represented in Asian MDS patients according to the Revised International Prognostic Scoring System. Next, we investigated whether differences in prognostic risk scores could find their origin in differential cytogenetic profiles. We found that 5q deletion (del(5q)) aberrations and mutations in TET2, SF3B1, SRSF2 and IDH1/2 are more frequently reported in Western MDS patients while trisomy 8, del(20q), U2AF1 and ETV6 mutations are more frequent in Asian MDS patients. Treatment approaches differ between Western and Asian countries owing to the above discrepancies, but the overall survival rate within each prognostic group is similar for Western and Asian MDS patients. Altogether, our study highlights greater risk MDS in Asians supported by their cytogenetic profile. [ABSTRACT FROM AUTHOR]

Abstract: Loss of material from chromosome arm 5q is a common finding in patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Fluorescence in situ hybridization with a panel of different types of probes, used as a complement to conventional cytogenetics, revealed that 7 of 148 patients (4.7%) with abnormalities of chromosome 5 had an i(5)(p10), an idic(5)(q11), or a structurally rearranged i(5)(p10). Three patients had MDS and four had AML. Six of the patients were female, and one was male; age at diagnosis ranged from 56 to 85 years. All patients but one had a complex karyotype. Isochromosome of the short arm of chromosome 5 and its related abnormalities such as idic(5)(q11) and structurally rearranged i(5)(p10) are rare but recurrent abnormalities; their identification requires a combination of conventional and molecular cytogenetic techniques. The biological and clinical significance cannot yet be assessed, not only because too few cases have been described but also because these abnormalities are usually part of a complex karyotype. [Copyright &y& Elsevier]

Secondary acute lymphoblastic leukemia (sALL) following chemotherapy and/or radiotherapy of previous malignancies represents 2–10% of all cases of ALL. A 72-year-old female patient was diagnosed with acute lymphoblastic leukemia following chemotherapy for a diffuse large B cell lymphoma. Banding cytogenetics showed a t(t(5;11)(q23–31;q23) in 20 of the 21 metaphases examined and fluorescent in situ hybridization confirmed rearrangement of MLL . Long distance inverse-polymerase chain reaction revealed an in-frame fusion between 5′ MLL and 3′ PRRC1 . Sixty-five cases of sALL associated with 11q23/ MLL rearrangement, including 47 with a t(4;11)(q21;q23), were retrieved from the literature. Drug regimen used to treat the primary neoplasm was available for 54 patients; 52 had received a topoisomerase II inhibitor, known to induce MLL rearrangement. [ABSTRACT FROM AUTHOR]

Abstract: We report the case of a 74-year-old man who sought care for de novo myelodysplastic syndrome (RAEB-1). Conventional cytogenetic techniques showed a karyotype with two different deletions of the long arm of chromosome 5 distributed in three clones: 46,XY,del(1)(p34),del(5)(q14q23)[2]/46,XY,del(1)(p34),del(5)(q14q34)[10]/46,idem,inv(5)(q?11q?34)[7]. Precise characterization of the breakpoints, delineation of the deleted regions, identification of the complex intrachromosomal rearrangement of chromosome 5, and sequential accumulation of chromosomal abnormalities were elucidated by several fluorescence in situ hybridization analyses. We also assessed the clinical, biological, and cytogenetic evolution under lenalidomide treatment and after its interruption. [ABSTRACT FROM AUTHOR]

Abstract: The detection of chromosome abnormalities by conventional cytogenetics, now combined with analyses using fluorescence in situ hybridization (FISH), is an important component in assessing the risk stratification of acute lymphoblastic leukemia (ALL). Identification of specific chromosome abnormalities led to the recognition of genetic subgroups based on modal chromosomal number, reciprocal translocations in B-cell ALL, or both. We report here the cytogenetic analysis of 208 patients with pre-B and B-cell ALL referred to a single laboratory between 1981 and 2008. Chromosome abnormalities were observed in 82.9% of L1/L2 ALL patients and in 83.3% of L3 patients with successful analysis at diagnosis. The proportion of diploid karyotypes tended to decrease during the period of study, from 26% to 13%, in association with technical progress and the introduction of FISH techniques. As previously reported, the incidence of high hyperdiploidy (51–67 chromosomes) was higher among children, whereas pseudodiploidy and hypodiploidy were higher among those >15 years of age. Structural chromosome abnormalities were more frequently observed among patients older than 15 years than in children (75.9% vs. 68.5%, respectively). As previously reported, t(9;22)(q34;q11) and t(12;21)(p13;q21) were the most frequent structural rearrangements among adults (26.9%) and children (19.7%), respectively. Almost 17% of the patients studied at diagnosis had further cytogenetic analyses at relapse, the majority showing clonal evolution toward a more complex karyotype. Although the detection of chromosome abnormalities by conventional cytogenetics and FISH techniques is an important tool in assessing risk stratification of ALL, some patients lack abnormalities with clinical relevance. The use of array comparative genomic hybridization (aCGH) offers an alternative for identifying copy number alterations, but cannot detect balanced chromosomal rearrangements. [Copyright &y& Elsevier]

Abstract: Chromosomal rearrangements involving the MLL gene have been associated with many different types of hematological malignancies. Most of them are easily recognized by conventional cytogenetics. However, in some cases, complex, unusual or cryptic rearrangements make the MLL involvement difficult or impossible to be detected by conventional cytogenetics. Fluorescent in situ hybridization with a panel of probes coupled with long distance inverse-PCR was used to identify chromosomal rearrangements involving the MLL gene. Seven unusual chromosomal rearrangements were identified, including two complex translocations, three insertions of material of chromosome 11 in another chromosome and one insertion of chromosome material into the MLL gene. Conventional cytogenetics showed three patients to have a deletion of 11q; one had an unexpected t(6;11)(q27;q23) whereas the other two patients had also an insertion of MLL material in another chromosome. Concurrent 3′ deletion in the MLL rearrangement was observed in two patients. We recommend a systematic approach to be used in all cases of acute leukemia starting with FISH analyses using a commercially available MLL split signal probe. Should an abnormality be discovered, the analysis has to be completed by further molecular cytogenetic and genomic PCR methods in order to unravel the recombination mechanism. [Copyright &y& Elsevier]