Zurück zur Übersicht
| Blood. 2020 Apr 29. pii: 454702. doi: 10.1182/blood.2019003062 |
| Human erythroleukemia genetics and transcriptomes identify master transcription factors as functional disease drivers. |
| Fagnan A1, Bagger FO2, Piqué-Borràs MR3, Ignacimouttou C4, Caulier A5, Lopez C6, Robert E7, Uzan B8, Gelsi-Boyer V9, Aid Z10, Thirant C11, Moll U12, Tauchmann S13, Kurtovic-Kozaric A14, Maciejewski JP15, Dierks C16, Spinelli O17, Salmoiraghi S18, Pabst T19, Shimoda K20, Deleuze V21, Lapillonne H22, Sweeney C23, Mansat-De Mas V24, Leite B25, Kadri Z26, Malinge S27, de Botton S28, Micol JB29, Kile BT30, Carmichael CL31, Iacobucci I32, Mullighan CG33, Carroll MP34, Valent P35, Bernard OA36, Delabesse E37, Vyas P38, Birnbaum D39, Anguita E40, Garcon L41, Soler E42, Schwaller J43, Mercher T44 |
 Author information
|
|
Abstract Acute erythroleukemia (AML-M6 or AEL) 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 three genetic AEL subgroups including TP53-mutated, epigenetic regulator-mutated (e.g. DNMT3A, TET2 or IDH2), and undefined cases with low mutational burden. We established an erythroid vs. myeloid transcriptomics-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, more than 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 indicates 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. |
|
Copyright © 2020 American Society of Hematology. |
|
Publikations ID: 32350520 Quelle: öffnen |
Author information
Schnellinfo
-- Cancer Care
-- Kliniken und Partner
-- CCC Cancer School
-- Young CCC
-- CCC Tumorboards
-- CCC Forschungscluster
-- CCC Units
-- CCC Platforms
-- SOPs / Leitlinien
-- Kontakt
Featured
