Human erythroleukemia genetics and transcriptomes identify master transcription factors as functional disease drivers

Alexandre Fagnan, Frederik Otzen Bagger, Maria Riera Piqué-Borràs, Cathy Ignacimouttou, Alexis Caulier, Cécile K. Lopez, Elie Robert, Benjamin Uzan, Véronique Gelsi-Boyer, Zakia Aid, Cécile Thirant, Ute Moll, Samantha Tauchmann, Amina Kurtovic-Kozaric, Jaroslaw Maciejewski, Christine Dierks, Orietta Spinelli, Silvia Salmoiraghi, Thomas Pabst, Kazuya ShimodaVirginie Deleuze, Hélène Lapillonne, Connor Sweeney, Véronique De Mas, Betty Leite, Zahra Kadri, Sébastien Malinge, Stéphane de Botton, Jean Baptiste Micol, Benjamin Kile, Catherine L. Carmichael, Ilaria Iacobucci, Charles G. Mullighan, Martin Carroll, Peter Valent, Olivier A. Bernard, Eric Delabesse, Paresh Vyas, Daniel Birnbaum, Eduardo Anguita, Loïc Garçon, Eric Soler, Juerg Schwaller, Thomas Mercher

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)698-714
Number of pages17
Issue number6
Publication statusPublished - 6 Aug 2020
Externally publishedYes


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