@misc{10481/57409,
year = {2019},
url = {http://hdl.handle.net/10481/57409},
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 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.},
organization = {Financial support for this work was obtained from the European
Research Council (CoG-2014-646903 and PoC-2018-811220)
and the Generalitat de Catalunya (SGR330 and PERIS 2017-
2019) to PM, the Spanish Ministry of Economy and
Competitiveness (SAF2016-80481-R and SAF2016-76758-R)
to PM and IV, the Spanish Association against Cancer (AECCCI-
2015) and Fero Foudation to CB, the Health Institute Carlos
III (ISCIII/FEDER, PI17/01028 and PI17/01028) to CB and
PJR, the NIHR GOSH BRC and Great Ormond Street Hospital
Children's Charity to J.dB, and Bloodwise and Cancer Research
UK to BG. 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). RV-M is supported by
a Torres Quevedo fellowship from the Spanish Ministry of Science
and Innovation (PTQ-16-08623). P.M is an investigator of the
Spanish Cell Therapy cooperative network (TERCEL).},
publisher = {Ferrata Storti Foundation},
title = {Enhanced hemato-endothelial specification during human embryonic differentiation through developmental cooperation between AF4-MLL and MLL-AF4 fusions},
doi = {10.3324/haematol.2018.202044},
author = {Bueno, Clara and Real Luna, Pedro José},
}