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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

FLT3-N676K drives acute myeloid leukemia in a xenograft model of KMT2A-MLLT3 leukemogenesis

Project description:Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements. Herein, we show that co-expression of FLT3-N676K and KMT2A-MLLT3 in human CD34+ cord blood cells primarily cause acute myeloid leukemia (AML) and rarely acute lymphoblastic leukemia (ALL) in immunodeficient mice. By contrast, expression of KMT2A-MLLT3 alone cause ALL, double-positive leukemia (DPL, expressing both CD33 and CD19), or bilineal leukemia (BLL, comprised of distinct myeloid and lymphoid leukemia cells), and rarely AML. Further, AML could only be serially propagated with maintained immunophenotype in secondary recipients when cells co-expressed KMT2A-MLLT3 and FLT3-N676K. Consistent with the idea that activated signaling would allow myeloid cells to engraft and maintain their self-renewal capacity, in a secondary recipient, a de novo KRAS-G13D was identified in myeloid cells previously expressing only KMT2A-MLLT3. Gene expression profiling revealed that KMT2A-MLLT3 DPL had a highly similar gene expression profile to ALL, with both expressing key lymphoid transcription factors and ALL cell surface markers, in line with the DPL cells being ALL cells with aberrant expression of CD33. Taken together, our results highlight the need for constitutive active signaling mutations for driving myeloid leukemia in a human xenograft model of KMT2A-R acute leukemia.

2019-04-05 | GSE127492 | GEO

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

Project description:KMT2A-MLLT3, a fusion protein formed by the t(9;11) translocation in acute myeloid leukemia, is an epigenetic transcription factor that is known to regulate a unique leukemic gene expression profile. We show that rearranged during transfection (RET) proto-oncogene is highly overexpressed in the KMT2A-MLLT3 subgroup. In addition to biochemical studies, the RNA-seq and ATAC seq analyses have been performed in KMT2A-MLLT3 positive MOLM-13 AML cell line, compared to the umbilical cord blood-driven CD34+ hematopoietic stem progenitor cells.

2024-03-04 | GSE241867 | GEO

KMT2A-rearranged leukemia proteomics

Project description:Activating mutations in kinase/PI3K/RAS signaling pathways are common in acute leukemia with KMT2A rearrangements (KMT2A-R). These mutations are often subclonal and their biological impact remain unclear. Using a retroviral acute myeloid leukemia model, we demonstrate that NRASG12D, FLT3ITD, and FLT3N676K accelerates KMT2A-MLLT3 leukemia onset. Importantly, also the presence of subclonal FLT3N676K in KMT2A-R leukemic cells shorten disease latency, possibly by providing stimulatory factors such as Mif. Acquired de novo mutations in Braf, Cbl, Kras, and Ptpn11 were identified in KMT2A-MLLT3 driven leukemia and favored clonal expansion. KMT2A-MLLT3 leukemia with an activating mutation enforce Myc- and Myb transcriptional modules, whereas KMT2A-MLLT3 leukemias lacking activating mutations displayed upregulation of signal transduction pathways. Our results provide new insight into the biology of KMT2A-R leukemia and highlights the importance of activated signaling as a contributing driver in this disease.

2018-05-02 | PXD008213 | Pride

Gene Expression Profiles with Common Translocations in Acute Myeloid Leukemia (AML) using SAGE

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.

2005-11-30 | E-GEOD-3255 | biostudies-arrayexpress

Transcription profiling of human hematopoietic stem cell like fractions from individuals with the M2 subtype of acute myeloid leukemia

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.

2014-02-13 | GSE36592 | GEO

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

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

Copy number analysis in de novo and therapy-related myeloproliferative neoplasms

Project description:Loss of chromosome 7 and del(7q) [-7/del(7q)] are recurring cytogenetic abnormalities in hematologic malignancies, including acute myeloid leukemia and therapy-related myeloid neoplasms, and associated with an adverse prognosis. We performed SNP array analysis on de novo and therapy-related myeloid neoplasms and identified a 2.17 Mb commonly deleted segment on chromosome band 7q22.1 containing CUX1, a gene encoding a homeodomain-containing transcription factor. Haploinsufficiency of the highly conserved ortholog, cut, led to hemocyte overgrowth and tumor formation in Drosophila melanogaster. Similarly, haploinsufficiency of CUX1 gave human hematopoietic cells a significant engraftment advantage upon transplantation into immunodeficient mice. These data identify CUX1 as a conserved, haploinsufficient tumor suppressor frequently deleted in myeloid neoplasms. We performed SNP-array analysis of 34 primary patient samples with de novo or therapy-related myeloid leukemia and one acute myeloid leukemia cell line, UoCM1. For patient samples, DNA was obtained from the white blood cells of bone marrow or peripheral blood leukemia specimens. Cytogenetic analysis revealed clonal -7/del(7q) in 17 of the cases.

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

The neuronal homeobox transcription factor HMX3 is a crucial vulnerability in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia [RNAseq_MOLM13_HMX3_KD]

Project description:The KMT2A::MLLT3 fusion protein causes acute myeloid leukemia (AML) by activating the oncogenic transcription factor MECOM. However, MECOM expression occurs only in half of the cases. By integrating gene expression and enhancer activity data from patient cells, we identified neuronal homeobox transcription factor HMX3 as cell fate determining factor in MECOM-negative KMT2A::MLLT3 AML. HMX3 expression associated with younger age and KMT2A-rearranged leukemia in large AML cohorts (p<0.002). It was absent in other major genetic risk groups and healthy blood cells. Transcriptomic analyses revealed that HMX3 drives cancer-associated E2F, MYC, and cell cycle gene programs. Ectopic HMX3 expression completely inhibited monocytic but not granulocytic colony formation of healthy CD34+ cord blood cells. Its silencing in KMT2A::MLLT3 AML cell lines and patient cells resulted in cell cycle arrest, monocytic differentiation, and apoptosis. Thus, HMX3 is a leukemia-specific vulnerability that enhances proliferation and blocks differentiation of MECOM-negative KMT2A::MLLT3 leukemia.

2024-12-13 | GSE242962 | GEO

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