Enhanced hemato-endothelial specification during human embryonic differentiation through developmental cooperation between AF4-MLL and MLL-AF4 fusions
Bueno, Clara (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Calero-Nieto, Fernando (Department of Hematology. Cambridge Institute for Medical Research and Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute. University of Cambridge)
Wang, X. (Department of Hematology. Cambridge Institute for Medical Research and Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute. University of Cambridge)
Valdés-Mas, Rafael (Dreamgenics S.L. Oviedo)
Gutiérrez-Agüera, Francisco (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Roca Ho, Heleia (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Ayllon, Veronica (Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica)
Real, P. J. (Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica)
Arambilet Mobilla, David (Institut Hospital del Mar d'Investigacions Mèdiques)
Espinosa, Lluis (Institut Hospital del Mar d'Investigacions Mèdiques)
Torres, Raul (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Agraz-Doblás, Antonio (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Varela, Ignacio (Universidad de Cantabria. Departamento de Biología Molecular)
De Boer, J. (University College London Great Ormond Street Institute of Child Health. Cancer Section)
Bigas Salvans, Anna (Institut Hospital del Mar d'Investigacions Mèdiques)
Gottgens, B. (Department of Hematology. Cambridge Institute for Medical Research and Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute. University of Cambridge)
Marschalek, Rolf (Institute of Pharmaceutical Biology. Goethe-University)
Menéndez Bujan, Pablo (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Universitat Autònoma de Barcelona

Data:	2019
Resum:	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 contribution 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 advantage 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 fusionexpressing hemato-endothelial precursors specified into significantly higher numbers of both hematopoietic and endothelial-committed cells, irrespective of the differentiation protocol used and without hijacking survival/proliferation. Functional analysis of differentially expressed genes and differentially enriched H3K79me3 genomic regions by RNA-sequencing and H3K79me3 chromatin immunoprecipitation-sequencing, respectively, confirmed 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 development.
Ajuts:	Agencia Estatal de Investigación SAF2016-80481-R Agencia Estatal de Investigación SAF2016-76758-R Instituto de Salud Carlos III PI17-01028 Ministerio de Ciencia e Innovación PTQ-16-08623 European Commission 646903 European Commission 811220
Nota:	Altres ajuts: RM and PM were also supported by the Deutsche José Carreras Leukämie Stiftung. PM also acknowledges financial support from the Obra Social La Caixa-Fundaciò Josep Carreras. R-T-R is supported by a fellowship from the Spanish Association of Cancer Research (AECC).
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Animals ; Apoptosis ; Cell Cycle ; Cell Differentiation ; Coculture Techniques ; Embryonic Development ; Endothelial Cells ; Hematopoiesis ; Hematopoietic Stem Cells ; Histones ; Human Embryonic Stem Cells ; Humans ; Methylation ; Mice ; Mice, Knockout ; Myeloid-Lymphoid Leukemia Protein ; Oncogene Proteins, Fusion
Publicat a:	Haematologica, Vol. 104 Núm. 6 (2019) , p. 1189-1201, ISSN 1592-8721

DOI: 10.3324/haematol.2018.202044
PMID: 30679325

13 p, 3.9 MB

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