Effects of the leukemia-associated AML1-ETO protein on hematopoietic stem and progenitor cells

Nimer, Stephen D.; Moore, Malcolm A.S.

doi:10.1038/sj.onc.1207673

Cited by 51 publications

(43 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The current view is that despite the inability of the fusion oncoprotein ETV6/RUNX1 to induce leukemic transformation on its own, the ETV6/RUNX1 fusion constitutes the initiating mutation in ETV6/RUNX1-positive leukemogenesis. [13][14][15][16] The identification of leukemia-initiating and -propagating cells in ETV6/RUNX1-positive ALL has recently corroborated this insight. 17 18 At relapse, additional alterations of chromosomes 12 and 21 are often detected in leukemic cells as well (85%).…”

Section: Introductionmentioning

confidence: 53%

Copy number genome alterations are associated with treatment response and outcome in relapsed childhood ETV6/RUNX1-positive acute lymphoblastic leukemia

et al. 2013

View full text Add to dashboard Cite

© F e r r a t a S t o r t i F o u n d a t i o nations are most likely required for ETV6/RUNX1-positive leukemogenesis and might be important for the differences in clinical outcome. More than 80% of initial ETV6/RUNX1-positive ALL display additional genetic alterations of the ETV6 and RUNX1 gene loci in fluorescence in situ hybridization (FISH) analyses. These include deletions of the untranslocated ETV6 gene (70%), an extra copy of RUNX1 (23%) and duplication of the derivative chromosome der(21) t(12;21) (10%). 18 At relapse, additional alterations of chromosomes 12 and 21 are often detected in leukemic cells as well (85%). 19 Current genome wide high resolution analyses of DNA copy number alterations (CNA) have identified numerous genetic alterations in childhood ALL. [20][21][22][23] In initial ETV6/RUNX1-positive ALL, genes related to B-lymphocyte development and differentiation, cell cycle regulation, tumor suppression and apoptosis are recurrently affected. 20,21,[24][25][26][27] Recent DNA copy number analyses on matched initial diagnosis and relapse ALL samples revealed that CNA acquired at relapse primarily affect genes implicated in cell cycle regulation, B-cell development, drug metabolism and drug response. 25,28,29 In the present study, leukemic cell DNA from 51 patients with a first relapse of ETV6/RUNX1-positive ALL enrolled in and treated according to the ALL-REZ BFM relapse trials were examined by whole genome array comparative genomic hybridization (CGH) for cooperating genetic lesions. This cohort represents the largest number of patients analyzed so far, enabling the investigation of an association between identified CNA and relapse-specific clinical and prognostic parameters for the first time. Methods Patients and samplesLeukemic bone marrow samples from 51 patients with first relapse of an ETV6/RUNX1-positive BCP-ALL were collected at relapse diagnosis after written informed consent was obtained from the patients, their parents or guardians in accordance with the ethical committee of the Charité and the declaration of Helsinki. All patients were enrolled in and treated according to ALL-REZ relapse trials 90, 95/96, and 2002 of the BFM study group, which were approved by the Institutional Review Boards of the Charité and the FU-Berlin, Germany. Diagnostic bone marrow samples were selected to contain >60% leukemic cells prior to further enrichment by Ficoll-density gradient separation of mononuclear cells. The presence of the ETV6/RUNX1 fusion was detected by reverse transcriptase polymerase chain reaction analysis as described previously. 9 DNA isolationLeukemic cell samples were prepared and DNA isolated from bone marrow or peripheral blood mononuclear cells of all patients and of 20 healthy controls, serving as gender-specific control DNA, as described previously. 30 All DNA samples were amplified using the GenomePlex Whole Genome Amplification Kit (SigmaAldrich Chemie GmbH, Munich, Germany) following the manufacturer's directions. Array comparative genomic hybridizationArray CGH...

show abstract

Section: Introductionmentioning

confidence: 53%

Copy number genome alterations are associated with treatment response and outcome in relapsed childhood ETV6/RUNX1-positive acute lymphoblastic leukemia

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Most cases of acute promyelocytic leukemia a subtype of acute myeloid leukemia (AML), for instance, are associated with a t(15;17) chromosomal rearrangement that results in the production of the PML-RARA fusion-type oncoprotein (Tallman and Altman, 2008). Similarly, another subtype of AML is associated with a t(8;21) rearrangement, resulting in the production of the oncogenic RUNX1-CBFA2T1 protein (Nimer and Moore, 2004).…”

Section: Introductionmentioning

confidence: 99%

Array-based genomic resequencing of human leukemia

et al. 2010

View full text Add to dashboard Cite

To identify oncogenes in leukemias, we performed largescale resequencing of the leukemia genome using DNA sequence arrays that determine B9 Mbp of sequence corresponding to the exons or exon-intron boundaries of 5648 protein-coding genes. Hybridization of genomic DNA from CD34-positive blasts of acute myeloid leukemia (n ¼ 19) or myeloproliferative disorder (n ¼ 1) with the arrays identified 9148 nonsynonymous nucleotide changes. Subsequent analysis showed that most of these changes were also present in the genomic DNA of the paired controls, with 11 somatic changes identified only in the leukemic blasts. One of these latter changes results in a Met-to-Ile substitution at amino-acid position 511 of Janus kinase 3 (JAK3), and the JAK3(M511I) protein exhibited transforming potential both in vitro and in vivo. Further screening for JAK3 mutations showed novel and known transforming changes in a total of 9 out of 286 cases of leukemia. Our experiments also showed a somatic change responsible for an Arg-to-His substitution at amino-acid position 882 of DNA methyltransferase 3A, which resulted in a loss of DNA methylation activity of 450%. Our data have thus shown a unique profile of gene mutations in human leukemia.

show abstract

“…Expression of the AML1-ETO oncofusion protein in hematopoietic cells results in a stage-specific arrest of maturation and increased cell survival, predisposing cells to develop leukemia. 3 Whereas the AML1-ETO translocation is usually observed in AML subtype M2, the inversion of chromosome 16, inv(16)(p13q22), is associated with AML-M4Eo. 4 This inversion generates a chimeric gene CBFb-MYH11, which encodes a fusion protein between CBFb and smooth muscle myosin heavy chain (SMMHC/MYH11).…”

Section: Introductionmentioning

confidence: 99%

CBFB–MYH11/RUNX1 together with a compendium of hematopoietic regulators, chromatin modifiers and basal transcription factors occupies self-renewal genes in inv(16) acute myeloid leukemia

et al. 2013

View full text Add to dashboard Cite

Different mechanisms for CBFb-MYH11 function in acute myeloid leukemia with inv(16) have been proposed such as tethering of RUNX1 outside the nucleus, interference with transcription factor complex assembly and recruitment of histone deacetylases, all resulting in transcriptional repression of RUNX1 target genes. Here, through genome-wide CBFb-MYH11-binding site analysis and quantitative interaction proteomics, we found that CBFb-MYH11 localizes to RUNX1 occupied promoters, where it interacts with TAL1, FLI1 and TBP-associated factors (TAFs) in the context of the hematopoietic transcription factors ERG, GATA2 and PU.1/SPI1 and the coregulators EP300 and HDAC1. Transcriptional analysis revealed that upon fusion protein knockdown, a small subset of the CBFb-MYH11 target genes show increased expression, confirming a role in transcriptional repression. However, the majority of CBFb-MYH11 target genes, including genes implicated in hematopoietic stem cell self-renewal such as ID1, LMO1 and JAG1, are actively transcribed and repressed upon fusion protein knockdown. Together these results suggest an essential role for CBFb-MYH11 in regulating the expression of genes involved in maintaining a stem cell phenotype.

show abstract

Effects of the leukemia-associated AML1-ETO protein on hematopoietic stem and progenitor cells

Cited by 51 publications

References 57 publications

Copy number genome alterations are associated with treatment response and outcome in relapsed childhood ETV6/RUNX1-positive acute lymphoblastic leukemia

Copy number genome alterations are associated with treatment response and outcome in relapsed childhood ETV6/RUNX1-positive acute lymphoblastic leukemia

Array-based genomic resequencing of human leukemia

CBFB–MYH11/RUNX1 together with a compendium of hematopoietic regulators, chromatin modifiers and basal transcription factors occupies self-renewal genes in inv(16) acute myeloid leukemia

Contact Info

Product

Resources

About