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Genome-wide Genotyping of Acute Myeloid Leukemia with Translocation t(9;11)(p22;q23) Reveals Novel Recurrent Genomic Alterations

ABSTRACT: To identify cooperating lesions in de novo and therapy-related acute myeloid leukemia (t-AML) with translocation t(9;11)(p22;q23) we performed high-resolution SNP-array profiling on 40 leukemia samples [de novo: n=22; t-AML: n=16; unknown: n=2]. A mean of 1.73 copy number alterations (CNAs)/case were identified with no differences between de novo and t-AML cases. We identified a novel minimally deleted region (MDR) at 7q36.1-q36.2 partly overlapping with a MDR previously identified in core-binding factor AML; MLL3 was the only gene affected in both regions. In addition, a recurrent gain was found at 13q21.33-q22.1 harboring the potential oncogene KLF5. Sequence/expression analysis of selected candidate genes revealed deregulated EVI1 at high frequency (50%). Copy-neutral loss-of-heterozygosity (CN-LOH) was absent in the paired cohort Further analysis of the candidate genes might provide novel insights into the pathogenesis of t(9;11) AML SNP genotyping was performed on 40 de novo and therapy-related MLL-MLLT3-rearranged acute myeloid leukemia samples; Germline control DNA from remission bone marrow or peripheral blood was available for paired analysis in 15 patients. Data were processed using reference alignment, dChipSNP and circular binary segmentation.

ORGANISM(S): Homo sapiens

SUBMITTER: Michael Kuehn

PROVIDER: E-GEOD-46745 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Genome-wide Genotyping of Acute Myeloid Leukemia with Translocation t(9;11)(p22;q23) Reveals Novel Recurrent Genomic Alterations

Project description:To identify cooperating lesions in de novo and therapy-related acute myeloid leukemia (t-AML) with translocation t(9;11)(p22;q23) we performed high-resolution SNP-array profiling on 40 leukemia samples [de novo: n=22; t-AML: n=16; unknown: n=2]. A mean of 1.73 copy number alterations (CNAs)/case were identified with no differences between de novo and t-AML cases. We identified a novel minimally deleted region (MDR) at 7q36.1-q36.2 partly overlapping with a MDR previously identified in core-binding factor AML; MLL3 was the only gene affected in both regions. In addition, a recurrent gain was found at 13q21.33-q22.1 harboring the potential oncogene KLF5. Sequence/expression analysis of selected candidate genes revealed deregulated EVI1 at high frequency (50%). Copy-neutral loss-of-heterozygosity (CN-LOH) was absent in the paired cohort Further analysis of the candidate genes might provide novel insights into the pathogenesis of t(9;11) AML

2014-05-22 | GSE46745 | GEO

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Enhancer-activated RET confers protection against oxidative stress to KMT2A-rearranged acute myeloid leukemia.

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KMT2A-rearranged leukemia proteomics

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2018-05-02 | PXD008213 | Pride

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Project description:SAGE was used to profile gene expression in leukemic myeloid progenitor cells of AML patients with t(8;21), t(15;17), t(9;11) and inv(16). Keywords: SAGE analysis of gene expression in leukemic myeloid progenitor cells isolated from bone marrow Bone marrow cells from 4 patients with de novo t(9;11), 3 with treatment-related t(9;11), and 5 each with inv(16), t(15;17), t(8;21) were used for the study. Each sample contained at least 75% affected cells with no other chromosome abnormalities at cytogenetic level. Mononuclear cells were purified from bone marrow cells for each sample, and CD15+ myeloid progenitor cells were isolated from these mononuclear cells. Poly A+ RNA were isolated from CD15+ myeloid progenitor cells of each sample for SAGE tag collection.

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Project description:AC133+ cells were prepared from bone marrow of individuals with acute myeloid leukemia (AML) with M2 subtype. Comparison was made between de novo AML and MDS-associated AML.

2003-10-09 | E-MEXP-25 | biostudies-arrayexpress

RNAi-mediated silencing of MLL-AF9 reveals leukemia-associated downstream targets and processes

Project description:The translocation t(9;11)(p22;q23) leading to the leukemogenic fusion gene MLL-AF9 is a frequent translocation in infant acute myeloid leukemia (AML). This study aimed to identify genes and molecular processes downstream of MLL-AF9 (alias MLL-MLLT3) which could assist to develop new targeted therapies for such leukemia with unfavorable prognosis. In the AML cell line THP1 which harbors this t(9;11) translocation, endogenous MLL-AF9 was silenced via siRNA while ensuring specificity of the knockdown and its efficiency on functional protein level. The differential gene expression profile was validated for leukemia-association by gene set enrichment analysis of published gene sets from patient studies and MLL-AF9 overexpression studies and revealed 425 differentially expressed genes. Gene ontology analysis was consistent with a more differentiated state of MLL-AF9 depleted cells, with involvement of a wide range of downstream transcriptional regulators and with defined functional processes such as ribosomal biogenesis, chaperone binding, calcium homeostasis and estrogen response. Besides potential new therapeutic targets, the described transcription profile shaped by MLL-AF9 provides an information source into the molecular processes altered in MLL aberrant leukemia.

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2014-02-13 | E-GEOD-36592 | biostudies-arrayexpress

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2012-11-24 | E-GEOD-42482 | biostudies-arrayexpress

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Project description:Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements (KMT2A-R). These mutations are often subclonal and their biological impact remains unclear. Using a retroviral acute myeloid mouse leukemia model, we demonstrate that FLT3ITD, FLT3N676K, and NRAS G12D accelerate KMT2A-MLLT3 leukemia onset. Subclonal FLT3N676K mutations also accelerate disease, possibly by providing stimulatory factors such as Mif. Acquired de novo mutations in Braf, Cbl, Kras, and Ptpn11 were identified in KMT2A-MLLT3 leukemia cells and favored clonal expansion. During clonal evolution, serial genetic changes at the KrasG12D locus was observed, consistent with a strong selective advantage of additional KrasG12D. KMT2A-MLLT3 leukemias with signaling mutations enforced Myc- and Myb transcriptional modules. Our results provide new insight into the biology of KMT2A-R leukemia with subclonal signaling mutations and highlights the importance of activated signaling as a contributing driver in this disease.

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