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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 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 fusion-expressing 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.
Fuente: Haematologica, 104 (6), 1189-1201 Jun 2019
Publisher: Ferrata Storti Foundation
Year of publication: 2019
No. of pages: 13
Publication type: Article
DOI: 10.3324/haematol.2018.202044
ISSN: 0390-6078,1592-8721
Spanish project: SAF2016-80481-R ; SAF2016-76758-R
Publication Url: https://www.doi.org/10.3324/haematol.2018.202044
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BUENO, CLARA
CALERO-NIETO, FERNANDO J.
WANG, XIAONAN
VALDÉS-MAS, RAFAEL
GUTIÉRREZ-AGÜERA, FRANCISCO
ROCA-HO, HELEIA
AYLLON, VERONICA
REAL, PEDRO J.
ARAMBILET, DAVID
ESPINOSA, LLUIS
TORRES-RUIZ, RAUL
AGRAZ DOBLAS, ANTONIO
IGNACIO VARELA EGOCHEAGA
BOER, JASPER DE
BIGAS, ANNA
GOTTGENS, BERTIE
MARSCHALEK, ROLF
MENENDEZ, PABLO
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