7 research outputs found
The ETO2 transcriptional cofactor maintains acute leukemia by driving a MYB/EP300âdependent stemness program
Transcriptional cofactors of the ETO family are recurrent fusion partners in acute leukemia. We characterized the ETO2 regulome by integrating transcriptomic and chromatin binding analyses in human erythroleukemia xenografts and controlled ETO2 depletion models. We demonstrate that beyond its wellâestablished repressive activity, ETO2 directly activates transcription of MYB, among other genes. The ETO2âactivated signature is associated with a poorer prognosis in erythroleukemia but also in other acute myeloid and lymphoid leukemia subtypes. Mechanistically, ETO2 colocalizes with EP300 and MYB at enhancers supporting the existence of an ETO2/MYB feedforward transcription activation loop (e.g., on MYB itself). Both smallâmolecule and PROTACâmediated inhibition of EP300 acetyltransferases strongly reduced ETO2 protein, chromatin binding, and ETO2âactivated transcripts. Taken together, our data show that ETO2 positively enforces a leukemia maintenance program that is mediated in part by the MYB transcription factor and that relies on acetyltransferase cofactors to stabilize ETO2 scaffolding activity
Développement de nouvelles approches thérapeutiques dans les leucémies aiguës myéloïdes
Les leucĂ©mies aiguĂ«s myĂ©loĂŻdes (LAM) sont des maladies gĂ©nĂ©ralement associĂ©es Ă un mauvais pronostic. Bien que la connaissance des bases molĂ©culaires des LAM ait progressĂ© au cours des derniĂšres annĂ©es, aucune thĂ©rapie spĂ©cifique n'est disponible. La frĂ©quente association des LAM7 (leucĂ©mies aiguĂ«s mĂ©gacaryoblastiques) avec une myĂ©lofibrose sĂ©vĂšre rend difficile la modĂ©lisation de cette maladie. Le laboratoire a donc dĂ©veloppĂ© une approche de xĂ©nogreffes de blastes leucĂ©miques de patients dans des souris immunodĂ©ficientes. Mon projet avait pour but de tester l'effet d'inhibiteurs d'Aurora (le DiMF, le MLN8237 et l'AZD1152) sur des blastes leucĂ©miques de LAM7 issus de patients et d'Ă©valuer s'ils inhibent leur prolifĂ©ration et induisent une mort cellulaire par apoptose. D'autre part, nous avons observĂ© une augmentation des cellules exprimant des marqueurs de diffĂ©renciation mĂ©gacaryocytaire terminale et une augmentation de la ploĂŻdie. Finalement, un traitement court des cellules leucĂ©miques in vitro retarde significativement le dĂ©veloppement de la maladie chez des souris receveuses secondaires confirmant l'intĂ©rĂȘt de ces inhibiteurs pour le traitement des LAM7.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF
Human erythroleukemia genetics and transcriptomes identify master transcription factors as functional disease drivers.
Acute erythroleukemia (AEL or acute myeloid leukemia [AML]-M6) is a rare but aggressive hematologic malignancy. Previous studies showed that AEL leukemic cells often carry complex karyotypes and mutations in known AML-associated oncogenes. To better define the underlying molecular mechanisms driving the erythroid phenotype, we studied a series of 33 AEL samples representing 3 genetic AEL subgroups including TP53-mutated, epigenetic regulator-mutated (eg, DNMT3A, TET2, or IDH2), and undefined cases with low mutational burden. We established an erythroid vs myeloid transcriptome-based space in which, independently of the molecular subgroup, the majority of the AEL samples exhibited a unique mapping different from both non-M6 AML and myelodysplastic syndrome samples. Notably, >25% of AEL patients, including in the genetically undefined subgroup, showed aberrant expression of key transcriptional regulators, including SKI, ERG, and ETO2. Ectopic expression of these factors in murine erythroid progenitors blocked in vitro erythroid differentiation and led to immortalization associated with decreased chromatin accessibility at GATA1-binding sites and functional interference with GATA1 activity. In vivo models showed development of lethal erythroid, mixed erythroid/myeloid, or other malignancies depending on the cell population in which AEL-associated alterations were expressed. Collectively, our data indicate that AEL is a molecularly heterogeneous disease with an erythroid identity that results in part from the aberrant activity of key erythroid transcription factors in hematopoietic stem or progenitor cells
Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models
Acute megakaryoblastic leukemia (AMKL) is a heterogeneous disease generally associated with poor prognosis. Gene expression profiles indicate the existence of distinct molecular subgroups, and several genetic alterations have been characterized in the past years, including the t(1;22)(p13;q13) and the trisomy 21 associated with GATA1 mutations. However, the majority of patients do not present with known mutations, and the limited access to primary patient leukemic cells impedes the efficient development of novel therapeutic strategies. In this study, using a xenotransplantation approach, we have modeled human pediatric AMKL in immunodeficient mice. Analysis of high-throughput RNA sequencing identified recurrent fusion genes defining new molecular subgroups. One subgroup of patients presented with MLL or NUP98 fusion genes leading to up-regulation of the HOX A cluster genes. A novel CBFA2T3-GLIS2 fusion gene resulting from a cryptic inversion of chromosome 16 was identified in another subgroup of 31% of non-Down syndrome AMKL and strongly associated with a gene expression signature of Hedgehog pathway activation. These molecular data provide useful markers for the diagnosis and follow up of patients. Finally, we show that AMKL xenograft models constitute a relevant in vivo preclinical screening platform to validate the efficacy of novel therapies such as Aurora A kinase inhibitors