T(15;21) translocation leading to the concurrent downregulation of RUNX1 and its transcription factor partner genes SIN3A and TCF12 in myeloid disorders
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Massimo Carella
PROVIDER: E-MTAB-3782 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Through a combined approach integrating RNA-Seq, SNP-array, FISH and PCR techniques, we identified two novel t(15;21) translocations leading to the inactivation of RUNX1 and its partners SIN3A and TCF12. One is a complex t(15;21)(q24;q22), with both breakpoints mapped at the nucleotide level, joining RUNX1 to SIN3A and UBL7-AS1 in a patient with myelodysplasia. The other is a recurrent t(15;21)(q21;q22), juxtaposing RUNX1 and TCF12, with an opposite transcriptional orientation, in three myeloid leukemia cases. Since our transcriptome analysis indicated a significant number of differentially expressed genes associated with both translocations, we speculate an important pathogenetic role for these alterations involving RUNX1.
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Project description:We apply the cellular reprogramming experimental paradigm to two disorders caused by symmetrical copy number variations (CNV) of 7q11.23 and displaying a striking combination of shared as well as symmetrically opposite phenotypes: Williams Beuren syndrome (WBS) and 7q microduplication syndrome (7dupASD). Through a uniquely large and informative cohort of transgene-free patient-derived induced pluripotent stem cells (iPSC), along with their differentiated derivatives, we find that 7q11.23 CNV disrupt transcriptional circuits in disease-relevant pathways already at the pluripotent state. These alterations are then selectively amplified upon differentiation into disease-relevant lineages, thereby establishing the value of large iPSC cohorts in the elucidation of disease-relevant developmental pathways. In addition, we functionally define the quota of transcriptional dysregulation specifically caused by dosage imbalances in GTF2I (also known as TFII-I), a transcription factor in 7q11.23 thought to play a critical role in the two conditions, which we found associated to key repressive chromatin modifiers. Finally, we created an open-access web-based platform (accessible at http://bio.ieo.eu/wbs/ ) to make accessible our multi-layered datasets and integrate contributions by the entire community working on the molecular dissection of the 7q11.23 syndromes. We reprogrammed skin fibroblasts from patients harbouring a 7q11.23 hemi-deletion (WBS, 4 patients; +1 atypical deletion, AtWBS) or microduplication (7dupASD; 2 patients), as well as from one unaffected relative and two unrelated controls, using integration-free mRNA-reprogramming, leading to the establishment of a total of 27 characterized iPSC clones. We profiled by aCGH each established iPSC clone as well as the original fibroblasts (for all patients and the unaffected relative).
2014-12-15 | E-GEOD-63028 | biostudies-arrayexpress
Project description:We report on two novel t(15;21) alterations [t(15;21)(q24;q22) and t(15;21)(q21;q22)], which led to concurrent disruption of RUNX1 and two translocation partner genes encoding for transcription factors (SIN3A, TCF12)
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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-12-15 | E-GEOD-63058 | biostudies-arrayexpress
Project description:We report on two novel t(15;21) alterations [t(15;21)(q24;q22) and t(15;21)(q21;q22)], which led to concurrent disruption of RUNX1 and two translocation partner genes encoding for transcription factors (SIN3A, TCF12) Examination of four different patients with myeloid disorders. 2 out of 4 have been analyzed by means RNAseq
2016-07-29 | E-GEOD-71551 | biostudies-arrayexpress
Project description:Analysis of the molecular etiologies of severe combined immunodeficiency (SCID) has led to important insights into the control of immune cell development. Most cases of SCID result from either X-linked or autosomal recessive inheritance of mutations in a known causative gene. However, in some cases, the molecular etiology remains unclear. To identify the cause of SCID in a patient known to lack the protein tyrosine phosphatase CD45, we utilized single nucleotide polymorphisms (SNP) Cytogenetics arrays; The patient’s mother was heterozygous for an inactivating mutation in CD45, while the paternal alleles exhibited no detectable mutations. The patient exhibited a single CD45 mutation identical to the maternal allele. Patient SNP array analysis revealed no change in copy number but loss of heterozygosity for the entire length of chromosome 1 (Chr1), indicating that disease was caused by uniparental disomy (UPD) with isodisomy of the entire maternal Chr1 bearing the mutant CD45 allele. Non-lymphoid blood cells and other mesoderm and ectoderm-derived tissues retained UPD of the entire maternal Chr1 in this patient who had undergone successful bone marrow transplantation. These findings represent the first reported case of SCID caused by UPD and suggest UPD should be considered in SCID and other recessive disorders, especially when the patient appears homozygous for an abnormal gene found in only one parent. Evaluation for alterations in other genes affected by UPD should also be considered in such cases. Affymetrix SNP Cytogenetics arrays were performed according to the manufacturer's directions on DNA extracted from cryopreserved sorted PMBC and buccal samples. Copy number and allele analysis of Affymetrix Cytogenetics arrays was performed for the patient's and his parent's samples.
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Project description:Our study provides evidence that JAK2, PDL1 and PDL2 are recurrently affected by structural and numerical aberrations in lymphoid neoplasms. The study highlights the role of PDL1/PDL2 in lymphoma progression. single case analysis
2013-04-13 | E-GEOD-46005 | biostudies-arrayexpress
Project description:Although information on the molecular pathogenesis of Waldenström’s Macroglobulinemia (WM) has greatly improved in recent years, the exact cellular origin and the mechanisms behind WM transformation from IgM MGUS remain undetermined. Here, we undertook an integrative phenotypic, molecular and genomic approach to study clonal B-cells from newly-diagnosed patients with IgM MGUS (n=22), smoldering (n=17), and symptomatic WM (n=10). Through principal-component-analysis of multidimensional flow cytometry data, we demonstrated overlapping phenotypic profiles between clonal B-cells from IgM MGUS, smoldering and symptomatic WM patients. Similarly, virtually no genes were significantly deregulated between FACS-sorted clonal B-cells from the three disease stages. Interestingly, while the transcriptome of the Waldenström’s clone was highly deregulated as compared to CD25-CD22+ normal B-cells, significantly less genes were differentially expressed and specific WM pathways down-regulated while comparing the transcriptome of the Waldenström’s clone vs. its normal phenotypic counterpart: CD25+CD22+dim B-cells. The frequency of specific copy number abnormalities [+4, del(6q23.3-6q25.3), +12, and +18q11-18q23] progressively increased from IgM MGUS and smoldering WM vs. symptomatic WM (18% vs. 20% and 73%, respectively; P =.008), suggesting a multistep transformation of clonal B-cells that albeit benign (i.e.: IgM MGUS and smoldering WM), already harbor the phenotypic and molecular signatures of the malignant Waldenström’s clone. Copy number analysis using the Affymetrix CytoScan 750K Array to study clonal B-cells from newly-diagnosed patients with IgM MGUS, smoldering, and symptomatic WM. Peripheral T-cells from paired and unpaired controls were also assessed.
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