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Acute Lymphoblastic Leukemia
Enhanced hemato-endothelial specification during human embryonic differentiation through developmental cooperation between AF4-MLL and MLL-AF4 fusions
Ferrata Storti Foundation
Haematologica 2019 Volume 104(6):1189-1201
Clara Bueno,1,2 Fernando J Calero-Nieto,3 Xiaonan Wang,3 Rafael Valdés-Mas,4 Francisco Gutiérrez-Agüera,1 Heleia Roca-Ho,1 Veronica Ayllon,5 Pedro J Real,5 David Arambilet,6 Lluis Espinosa,6,2 Raul Torres-Ruiz,1 Antonio Agraz-Doblas,1,7 Ignacio Varela,7 Jasper de Boer,8 Anna Bigas,6,2 Bertie Gottgens,3 Rolf Marschalek9 and Pablo Menendez1,2,10
1Josep Carreras Leukemia Research Institute and Department of Biomedicine, School of Medicine, University of Barcelona, Spain; 2Centro de Investigación Biomédica en Red de Cáncer (CIBER-ONC), ISCIII, Barcelona, Spain; 3Department of Hematology, Cambridge Institute for Medical Research and Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, UK; 4Dreamgenics S.L. Oviedo. Spain; 5GENyO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government and University of Granada, Department of Biochemistry and Molecular Biology, Granada, Spain; 6Programa de Cáncer, Instituto Hospital del Mar de Investigaciones Médicas. Barcelona. Spain; 7Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC-Sodercan), Departamento de Biología Molecular, Universidad de Cantabria, Santander, Spain; 8Cancer Section, UCL Great Ormond Street Institute of Child Health, London, UK; 9Institute of Pharmaceutical Biology, Goethe-University, Frankfurt, Germany and 10Instituciò Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
ABSTRACT
The t(4;11)(q21;q23) translocation is associated with high-risk infant pro-B-cell acute lymphoblastic leukemia and arises prenatally during embryonic/fetal hematopoiesis. The developmental/pathogenic con- tribution of the t(4;11)-resulting MLL-AF4 (MA4) and AF4-MLL (A4M) fusions remains unclear; MA4 is always expressed in patients with t(4;11)+ B-cell acute lymphoblastic leukemia, but the reciprocal fusion A4M is expressed in only half of the patients. Because prenatal leukemogenesis manifests as impaired early hematopoietic differentiation, we took advan- tage of well-established human embryonic stem cell-based hematopoietic differentiation models to study whether the A4M fusion cooperates with MA4 during early human hematopoietic development. Co-expression of A4M and MA4 strongly promoted the emergence of hemato-endothelial precursors, both endothelial- and hemogenic-primed. Double fusion- expressing hemato-endothelial precursors specified into significantly higher numbers of both hematopoietic and endothelial-committed cells, irrespec- tive of the differentiation protocol used and without hijacking survival/pro- liferation. Functional analysis of differentially expressed genes and differen- tially enriched H3K79me3 genomic regions by RNA-sequencing and H3K79me3 chromatin immunoprecipitation-sequencing, respectively, con- firmed a hematopoietic/endothelial cell differentiation signature in double fusion-expressing hemato-endothelial precursors. Importantly, chromatin immunoprecipitation-sequencing analysis revealed a significant enrichment of H3K79 methylated regions specifically associated with HOX-A cluster genes in double fusion-expressing differentiating hematopoietic cells. Overall, these results establish a functional and molecular cooperation between MA4 and A4M fusions during human hematopoietic develop- ment.
Correspondence:
CLARA BUENO
cbueno@carrerasresearch.org
PABLO MENENDEZ
pmenendez@carrerasresearch.org
Received: July 18, 2018. Accepted: January 21, 2019. Pre-published: January 24, 2019.
doi:10.3324/haematol.2018.202044
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/6/1189
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