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AF4-MLL in human embryonic hematopoietic development
fusion-expressing differentiating hESC (false discovery rate <0.1) (Figure 7C). As such, HOX-A genes were upreg- ulated in double fusion-expressing hematopoietic clono- genic progenitors (Online Supplementary Figure S3C). No differential enrichment of the repressive H3K4me2/3 mark was observed in either HOX-A or non-HOX genes in double fusion-expressing cells (Online Supplementary Figure
A
S4). Collectively, these data suggest that the deregulated expression of HOX-A genes in MLL leukemias may be imposed by the reciprocal A4M fusion through H3K79 methyltransferase activity. In support of this, a recent RNA-sequencing study performed in 42 infants with t(4;11)+ B-ALL enrolled in the Interfant treatment protocol, revealed that 45% of t(4;11)+ patients express the A4M
BC
Figure 6. Transcriptional transition towards a hematopoietic/endothelial gene signature in double fusion-expressing hemato-endothelial precursors. (A) Heatmap representation of hierarchical clustering of genes differentially expressed between empty vector (EV)-, single fusions- and double fusion-expressing hemato-endothe- lial precursors (HEP). Each column represents a technical replicate from three independent experiments. (B,C) Statistically significant functional categories (B) and cancer/leukemia-associated biofunctions (C) identified using Ingenuity Pathway Analysis on genes differentially expressed in single fusions-, and double fusion- expressing HEP relative to EV. They are ranked by z-score. Functional categories associated with “hematological system development and function” and “cardiovas- cular system development” are shown in bold. All significant biofunctions are associated with blood cell differentiation, homeostasis and migration/movement.
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