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An MLL-SEPT9 fusion and t(11;17)(q23;q25) associated with de novo myelodysplastic syndrome.

ABSTRACT: Rearrangements of the MLL gene at chromosome 11q23 are uncommon in de novo myelodysplastic syndrome (MDS). Here, we describe molecular findings in a patient with multilineage dysplasia and t(11;17)(q23;q25) who responded to decitabine therapy. Fluorescent in situ hybridization (FISH) demonstrated rearrangement of MLL, while RT-PCR analysis and sequencing identified the transcript fusion partner as SEPT9, a member of the septin family of GTPases. MLL-SEPT9 fusion appears to be rare, having been described to date in only seven cases of AML and not, to our knowledge, in MDS. Analysis of MLL-septin family member fusion products such as the one seen here may provide further insights into the etiology of myeloid neoplasia, and MLL-SEPT9 fusion may be worth seeking in other cases of MLL rearrangements with a translocation partner on chromosome 17q.

SUBMITTER: Kreuziger LM

PROVIDER: S-EPMC2768487 | biostudies-literature | 2007 Aug

REPOSITORIES: biostudies-literature

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An MLL-SEPT9 fusion and t(11;17)(q23;q25) associated with de novo myelodysplastic syndrome.

Kreuziger Lisa M Baumann LM Porcher Julie Cliff JC Ketterling Rhett P RP Steensma David P DP

Leukemia research 20070123 8

Rearrangements of the MLL gene at chromosome 11q23 are uncommon in de novo myelodysplastic syndrome (MDS). Here, we describe molecular findings in a patient with multilineage dysplasia and t(11;17)(q23;q25) who responded to decitabine therapy. Fluorescent in situ hybridization (FISH) demonstrated rearrangement of MLL, while RT-PCR analysis and sequencing identified the transcript fusion partner as SEPT9, a member of the septin family of GTPases. MLL-SEPT9 fusion appears to be rare, having been d ...[more]

PMID: 17250889

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MLL-SEPT5 Fusion Transcript in Myelodysplastic Syndrome Patient With t(11;22)(q23;q11).

Project description:Objectives: This study aimed to identify unknown mixed lineage leukemia (MLL) translocation partner genes in a de novo patient with myelodysplastic syndrome (MDS) with t(11;22)(q23;q11) and investigate the clinical and molecular features of this patient. Methods: Bone marrow cells were assessed by karyotype analysis to reveal chromosomal abnormalities. Fluorescence in situ hybridization (FISH) was performed to detect MLL gene rearrangement using an MLL-specific break-apart probe. LDI-PCR and RT-PCR were performed, and the PCR products were sequenced using an Illumina MiSeq sequencer (Illumina, San Diego, CA, USA). The sequence data of the PCR products were analyzed using bioinformatics tools. Meanwhile, clinical data were collected to evaluate the prognosis of the patient. Results: Chromosomal karyotype analysis showed that the karyotype of the patient was 46, XX, t(11;22)(q23;q11)[10]/46, XX[1]. Subsequently, FISH data confirmed MLL gene rearrangement in the patient. LDI-PCR precisely showed that SEPT5 was the MLL translocation partner gene. RT-PCR and sequencing analysis disclosed the presence of MLL-SEPT5 fusion transcript and confirmed the fusion between MLL exon 8 and SEPT5 exon 3. Moreover, the patient had a recurrence shortly after allogeneic hematopoietic stem cell transplantation. Conclusion: Although the MLL-SEPT5 fusion transcript was occasionally described in acute myeloid leukemia, it was first identified in MDS. Patients with MLL-SEPT5 fusion gene exhibited a poor prognosis even with an aggressive treatment.

| S-EPMC8729882 | biostudies-literature

MSF (MLL septin-like fusion), a fusion partner gene of MLL, in a therapy-related acute myeloid leukemia with a t(11;17)(q23;q25).

Project description:MLL (ALL1, Htrx, HRX), which is located on chromosome band 11q23, frequently is rearranged in patients with therapy-related acute myeloid leukemia who previously were treated with DNA topoisomerase II inhibitors. In this study, we have identified a fusion partner of MLL in a 10-year-old female who developed therapy-related acute myeloid leukemia 17 months after treatment for Hodgkin's disease. Leukemia cells of this patient had a t(11;17)(q23;q25), which involved MLL as demonstrated by Southern blot analysis. The partner gene was cloned from cDNA of the leukemia cells by use of a combination of adapter reverse transcriptase-PCR, rapid amplification of 5' cDNA ends, and BLAST database analysis to identify expressed sequence tags. The full-length cDNA of 2.8 kb was found to be an additional member of the septin family, therefore it was named MSF (MLL septin-like fusion). Members of the septin family conserve the GTP binding domain, localize in the cytoplasm, and interact with cytoskeletal filaments. A major 4-kb transcript of MSF was expressed ubiquitously; a 1.7-kb transcript was found in most tissues. An additional 3-kb transcript was found only in hematopoietic tissues. By amplification with MLL exon 5 forward primer and reverse primers in MSF, the appropriately sized products were obtained. MSF is highly homologous to hCDCrel-1, which is a partner gene of MLL in leukemias with a t(11;22)(q23;q11.2). Further analysis of MSF may help to delineate the function of MLL partner genes in leukemia, particularly in therapy-related leukemia.

| S-EPMC26898 | biostudies-literature

De novo mutations in MLL cause Wiedemann-Steiner syndrome.

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Intellectual Disability in Two Brothers Caused by De Novo Novel Unbalanced Translocation (13;18) (q34,q23) and De Novo Microdeletion 6q25 Syndrome.

Project description:We report here two brothers with an intellectual disability (ID), dysmorphic features, speech delay, and congenital hypotonia, with chromosomal microarray confirmed. However, two different de novo chromosomal aberrations; unbalanced translocations (13;18) (q34,q23) were found in the elder boys and de novo 6q25 deletion in the second boy. The boy with 13q34 microdeletion and 18q23 microduplication suffered from ID, obesity, dysmorphic features, speech delay, and seizure while the one with 6q25 deletion presented with ID and speech delay. Both parents were tested and were normal. The third child had mild hypotonia at infancy, which improved later. Whole-exome sequencing (WES) showed the three boys carried a likely benign variant in MED12, inherited from the healthy, asymptomatic mother. The father suffered from rheumatoid arthritis and was on chemotherapy during the conception of the first two affected boys. This report places emphasis on the use of a chromosomal microarray in patients with ID, even with familial cases, and reports the paternal use of methotrexate.

| S-EPMC6984774 | biostudies-literature

Paternal origin of the de novo constitutional t(11;22)(q23;q11).

Project description:The constitutional t(11;22)(q23;q11) is a well-known recurrent non-Robertsonian translocation in humans. Although translocations generally occur in a random fashion, the break points of t(11;22)s are concentrated within several hundred base pairs on 11q23 and 22q11. These regions are characterized by palindromic AT-rich repeats (PATRRs), which appear to be responsible for the genomic instability. Translocation-specific PCR detects de novo t(11;22)s in sperm from healthy males at a frequency of 1/10(4)-10(5), but never in lymphoblasts, fibroblasts or other human somatic cell lines. This suggests that the generation of t(11;22) rearrangement is linked to gametogenesis, although female germ cells have not been tested. Here, we have studied eight cases of de novo t(11;22) to determine the parental origin of the translocation using the polymorphisms on the relevant PATRRs. All of the eight translocations were found to be of paternal origin. This result implicates a possible novel mechanism of sperm-specific generation of palindrome-mediated chromosomal translocations.

| S-EPMC2987363 | biostudies-literature

Acute mixed-lineage leukemia t(4;11)(q21;q23) generates an MLL-AF4 fusion product.

Project description:A chromosomal translocation, t(4;11)-(q21;q23), is associated with an aggressive mixed-lineage leukemia. A yeast artificial chromosome was used to clone the chromosomal breakpoint of this translocation in the RS4;11 cell line. The breakpoint sequences revealed an inverted repeat bordered by a consensus site for topoisomerase II binding and cleavage as well as chi-like elements. The der(11) chromosome encodes a fusion RNA and predicted chimeric protein between the 11q23 gene MLL and a 4q21 gene designated AF4. The sequence of the complete open reading frame for this fusion transcript reveals the MLL protein to have homology with DNA methyltransferase, the Drosophila trithorax gene product, and the "AT-hook" motif of high-mobility-group proteins. An alternative splice that deletes the AT-hook region of MLL was identified. AF4 is a serine- and proline-rich putative transcription factor with a glutamine-rich carboxyl terminus. The composition of the complete MLL-AF4 fusion product argues that it may act through either a gain-of-function or a dominant negative mechanism in leukemogenesis.

| S-EPMC47247 | biostudies-other

De novo myelodysplastic syndrome in a Rothmund-Thomson Syndrome patient with novel pathogenic <i>RECQL4</i> variants.

Project description:Rothmund-Thomson syndrome (RTS) is a rare autosomal-recessive disorder with clinical features consisting of rash, poikiloderma, sparse hair, short stature, juvenile cataracts, skeletal abnormalities, and cancer predisposition. Genetic studies involving detection of pathogenic RECQL4 variants provide the diagnostic certitude. Osteosarcoma was found in two-thirds RECQL4-mutated RTS patients, while hematological malignancies were rarely reported. The variant diversity of RECQL4 gene has not been fully identified and mutations associated with hematologic malignancies are not well described. In this study, we presented a pedigree of RTS from a Chinese family, among which the proband was diagnosed with de novo myelodysplastic syndrome (MDS). Comprehensive medical examination and chromosome karyotyping were performed on the proband. Whole exome sequencing (WES) was performed on the proband, his sister and his mother. The familial cosegregation of sequence variants derived from WES was conducted by polymerase chain reaction-based Sanger sequencing. Structures of candidate RECQL4 mutants were done by in silico analysis to assess pathogenicity. Three novel RECQL4 germline variants, including c.T274C, c.G3014A, and c.G801C, were identified by WES and validated by Sanger sequencing. Prediction of conformation indicated that the structural stability of human RECQL4 protein was largely affected with these variants. The co-occurring U2AF1 p.S34F and TP53 p.Y220C mutations might contribute to the development of MDS. Our study expands the mutational spectrum of RECQL4 and provides underlying molecular mechanism for the development of MDS in RTS patients.

| S-EPMC10205365 | biostudies-literature

Abrogation of RUNX1 gene expression in de novo myelodysplastic syndrome with t(4;21)(q21;q22).

Project description:The disruption of RUNX1 function is one of the main mechanisms of disease observed in hematopoietic malignancies and the description of novel genetic events that lead to a RUNX1 loss of function has been accelerated with the development of genomic technologies. Here we describe the molecular characterization of a new t(4;21)(q21;q22) in a de novo myelodysplastic syndrome that resulted in the deletion of the RUNX1 gene. We demonstrated by quantitative real-time RT-PCR an almost complete depletion of the expression of the RUNX1 gene in our t(4;21) case compared with CD34(+) cells that was independent of mutation or DNA methylation. More importantly, we explored and confirmed the possibility that this abrogation also prevented transactivation of RUNX1 target genes, perhaps confirming the genetic origin of the thrombocytopenia and the myelodysplastic features observed in our patient, and certainly mimicking what has been observed in the presence of the RUNX1/ETO fusion protein.

| S-EPMC3347656 | biostudies-literature

A case of KMT2A-SEPT9 fusion-associated acute megakaryoblastic leukemia.

Project description:Acute megakaryoblastic leukemia (AMKL) constitutes ∼5%-15% of cases of non-Down syndrome AML in children, and in the majority of cases, chimeric oncogenes resulting from recurrent gene rearrangements are identified. Based on these rearrangements, several molecular subsets have been characterized providing important prognostic information. One such subset includes a group of patients with translocations involving the KMT2A gene, which has been associated with various fusion partners in patients with AMKL. Here we report the molecular findings of a 2-yr-old girl with AMKL and t(11;17)(q23;25) found to have a KMT2A-SEPT9 fusion identified through targeted RNA sequencing. A KMT2A-SEPT9 fusion in this subset of patients has not previously been reported.

| S-EPMC6318764 | biostudies-literature

Three de novo variants in KMT2A (MLL) identified by whole exome sequencing in patients with Wiedemann-Steiner syndrome.

Project description:BackgroundWiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder characterized by short stature, hypertrichosis, intellectual disability, developmental delay, along with facial dysmorphism. WSS patients exhibit great phenotypic heterogeneities. Some variants in KMT2A (MLL) gene have been identified as the cause of WSS.MethodsWhole exome sequencing on the probands followed by Sanger sequencing validations in the family were applied to determine genetic variants. In silico analyses were used for predicting potential effects of the variants.ResultsWe identified three novel de novo heterozygous variants: c.883A>T (p.Lys295*), c.4171C>T (p.Gln1391*), and c.3499T>C (p.Cys1167Arg), in KMT2A gene from three unrelated Chinese WSS patients. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, these three variants were classified as pathogenic, pathogenic and likely pathogenic variant, respectively. By reviewing all the available cases with same mutated KMT2A regions as the three patients had, we found that in addition to the representative symptoms, our patients exhibited some sporadically observed symptoms, such as severe ophthalmological symptoms, endocardial fibroelastosis, cytomegalovirus infection, and feet eversion. We also revealed that variants in different KMT2A regions contribute to the phenotypic heterogeneity of WSS, highlighting challenges in the diagnosis of syndromic disorders spanning a broad phenotypic spectrum.ConclusionOur study would aid in further broadening our knowledge about the genotype-phenotype correlation of WSS.

| S-EPMC8580087 | biostudies-literature

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