Iveta Sarova

Involvement of deleted chromosome 5 in complex chromosomal aberrations in newly diagnosed myelodysplastic syndromes (MDS) is correlated with extremely adverse prognosis

MDS with complex chromosomal aberrations (CCA) are characterized by short survival and a high rate of transformation to AML. A comprehensive genome-wide analysis of bone-marrow cells of 157 adults with newly diagnosed MDS and CCA revealed a large spectrum of nonrandom genomic changes related to the advanced stages of MDS. Chromosome shattering, probably resulting from chromothripsis, was found in 47% of patients. Deleted chromosome 5 was unstable and often involved in different types of cryptic unbalanced rearrangements. No true monosomy 5 was observed. Patients with CCA involving deleted chromosome 5 had an extremely poor prognosis (median overall survival, 2 months).

A partial nontandem duplication of the MLL gene in four patients with acute myeloid leukemia

Unusual MLL gene rearrangements were found in bone marrow cells of four patients with acute myeloid leukemia. A combination of conventional and molecular cytogenetic methods were used to describe translocations t(9;12;11)(p22;p13;q23), t(11;19)(q23;p13.3), and t(10;11)(p12;23) and inverted insertion ins(10;11)(p12;q23.3q23.1). Partial nontandem duplication of the MLL gene was identified by reverse transcriptase-polymerase chain reaction in all cases. The duplication, which included MLL exons 2 through 8-9, was interrupted by a cryptic insertion of one or two exons from the respective MLL partner gene: MLLT10, MLLT3, or MLLT1.

The translocation t(2;11)(p21;q23) without MLL gene rearrangement—a possible marker of good prognosis in myelodysplastic syndrome patients

The translocation t(2;11)(p21;q23) is associated with de novo myelodysplastic syndromes (MDS) and has an overall frequency of approximately 1%. The outcome of MDS patients with this translocation is not clear until now, because most of the clinical data addressing the t(2;11)(p21;q23) has been collected without investigating the status of the mixed lineage leukemia (MLL) gene. In this report, we present seven new patients with MDS diagnosis and the t(2;11)(p21;q23) in bone marrow cells; all of them without MLL gene rearrangement. They were found in two databases consisting of 1185 patients of two Czech institutions. These patients tended to be younger and showed a strong male predominance. A cytological and histological assessment of bone marrow at diagnosis revealed only mild MDS with marked dysplasia in megakaryopoiesis. Similar to other primary abnormalities in MDS (e.g. deletion of 11q), the t(2;11)(p21;q23) was frequently associated with deletion of 5q. Our results stress the common clinicopathological features of this entity and indicate that the t(2;11)(p21;q23) may be associated with a good prognosis for MDS patients (median survival 72 months). Copyright

Characterization of chromosome 11 breakpoints and the areas of deletion and amplification in patients with newly diagnosed acute myeloid leukemia

Chromosome 11 abnormalities are found in many hematological malignancies. In acute myeloid leukemia (AML), a proto‐oncogene MLL (11q23.3) is frequently altered. However, rearrangements involving other regions of chromosome 11 have been reported. Therefore, we have characterized the chromosome 11 breakpoints and common deleted and amplified areas in the bone marrow or peripheral blood cells of newly diagnosed patients with AML. Using molecular–cytogenetic methods (multicolor fluorescence in situ hybridization (mFISH), multicolor banding (mBAND), microarrays, and FISH with bacterial artificial chromosome (BAC) probes, chromosome 11 abnormalities were delineated in 54 out of 300 (18%) newly diagnosed AML patients. At least 36 different chromosome 11 breakpoints were identified; two were recurrent (11p15.4 in the NUP98 gene and 11q23.3 in the MLL gene), and three were possibly nonrandom: 11p13 (ch11:29.31‐31.80 Mb), 11p12 (ch11:36.75‐37.49 Mb) and 11q13.2 (68.31‐68.52 Mb). One new MLL gene rearrangement is also described. No commonly deleted region of chromosome 11 was identified. However, some regions were affected more often: 11pter‐11p15.5 (n = 4; ch11:0‐3.52 Mb), 11p14.1‐11p13 (n = 4; ch11:28.00‐31.00 Mb) and 11p13 (n = 4; ch11:31.00‐31.50 Mb). One commonly duplicated (3 copies) region was identified in chromosomal band 11q23.3‐11q24 (n = 9; ch11:118.35‐125.00 Mb). In all eight cases of 11q amplification (>3 copies), only the 5′ part of the MLL gene was affected. This study highlights several chromosome 11 loci that might be important for the leukemogeneic process in AML.

Fusion of the additional sex combs like 1 and teashirt zinc finger homeobox 2 genes resulting from ider(20q) aberration in a patient with myelodysplastic syndrome.

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Recurrent chromosomal breakpoints in patients with myelodysplastic syndromes and complex karyotype versus fragile sites

The myelodysplastic syndromes (MDS) represent a heterogeeous group of clonal disorders characterized by a maturation efect in hematopoietic stem cells. Ineffective hematopoiesis leads o cytopenia, clonal instability and an increased risk of transformaion to acute myeloid leukemia (AML). Biologic and genetic tests, in ddition to cytogenetic and molecular cytogenetic analyses of bone arrow cells, are needed to confirm an MDS diagnosis to place he patient in the correct predictive risk group and to select the ost effective therapy. The MDS karyotype has been established s an independent prognostic factor for survival, for response to herapy and for estimating the probability of AML evolution [1]. lonal chromosomal aberrations are detected in the bone marow (BM) in ∼50% of newly diagnosed cases of MDS, and up to 0% of cases have complex chromosomal aberrations (CCA). CCA re defined as numerical or structural changes involving three or ore chromosomes and/or rearrangements with three or more hromosomal breaks that are strongly associated with a very poor rognosis. Recurrent chromosomal aberrations (del(5)(q), monoomy 7, del(20)(q) and trisomy 8) have been described in BM rom ∼50% of newly diagnosed MDS patients, frequently as a part f CCA. Recently, there have been several published reports of hromosomal breakpoints that are associated with cancer genesis nd progression that have confirmed the co-localization of these hromosomal breakpoints to known fragile sites (FS). Breakpoints ssociated with structural changes that are localized to the FS (comon or rare) may play a significant role in inactivation of tumor uppressor genes or activation of oncogenes. FS can be defined as eritable-specific loci on human chromosomes that exhibit nonandom gaps or breaks when chromosomes are exposed to specific ell culture conditions. Rare fragile sites (RFS) are identifiable in less han 5% of the population, while common fragile sites (CFS) are ntrinsic parts of normal chromosome structure that are present n all individuals. We applied microarray technology to analyze enomic structural aberrations in MDS patients with complex aryotypes to identify recurrent chromosomal breakpoints and to valuate and compare their potential associations with FS.