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C. Bueno et al.
fusion, and that HOX-A cluster genes are exclusively expressed in this AF4-MLL-expressing subgroup of t(4;11)+ patients, who do in fact have a significantly more favor- able clinical outcome.19
Discussion
From etiological and pathogenic standpoints, infant cancer is distinct from adult cancer and should be studied as a developmental disease.4,7,16 A biologically and clini- cally intriguing infant cancer is the t(4;11)+ B-ALL, which is associated with a dismal outcome.4,21,23 Evidence in sup- port of its prenatal origin comes from studies in monozy- gotic twins and archived blood spots, providing com- pelling evidence of a single prenatal cell as the origin for t(4;11),5 and also from recent genome-wide studies demonstrating that this infant leukemia has one of the lowest frequencies of somatic mutations of any sequenced cancer.55 The stable genome of these patients suggests that in infant developmental cancer, one “big- hit” might be sufficient to cause overt disease, support- ing a key contribution of the prenatal cell-of-origin dur- ing a critical developmental window of stem cell vulner- ability in leukemogenesis. However, despite its aggres-
siveness and short latency, our current understanding about its etiology, pathogenesis and cellular origin is still limited.2,4,14,16,52 Importantly, a recently developed xenograft model which represents the most bona fide model for t(4;11)+ B-ALL so far, has revealed the instruc- tive role of MLL-Af4 in cord blood-derived CD34+ cells.14
Studies using primary cells from t(4;11)+ B-ALL patients are incapable of addressing the developmental genesis of the hematopoietic system. Recent data suggest that fetal liver lymphoid-primed multipotent progenitors may pro- vide the developmental prerequisites for the initiation of t(4;11)+/MLL-AF4 infant leukemia.56 Because leukemogen- esis manifests as a blockage or altered cell differentiation, the hematopoietic differentiation of hESC may represent a promising in vitro model for studying the onset of hematopoiesis and the earliest events leading to the spec- ification of the hematopoietic cells.36 Previous studies have addressed the oncogenic role of leukemic fusion genes in hESC-derived hematopoiesis.57-59 We previously explored the developmental impact of the prenatal fusion MA4 in hESC hemato-endothelial development,10 and found that MA4 expression promotes the emergence of endothelial- primed HEP and further endothelial commitment, but hijacks the specification of hemogenic-primed HEP, impairing hematopoietic output.10
AB
Figure 7. H3K79 methylation profiles at genomic loci of MLL targets in MA4-, A4M- and double fusion-expressing human embryonic stem cell-derived blood deriv- atives. (A) Gene ontology enrichment of differential H3K79me3 peaks specific for double fusion-expressing cells. (B,C) Representative profiles for chromatin immuno- precipitation-sequencing using anti-H3K79me3 antibody at genomic regions of typical non-HOXA (B) and HOXA MLL targets (C).
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haematologica | 2019; 104(6)