Three infants are reported with a recognizable pattern of defects consisting of severe microcephaly, overlapping sutures, prominence of the occipital bone, and scalp rugae. This condition, which we think represents microhydranencephaly, appears to be produced by partial brain destruction during the second or third trimester, diminution in intracranial hydrostatic pressure, and subsequent collapse of the fetal skull. Several different causes for this condition have been suggested including partial disruption of the blood supply to the brain and prenatal viral infection.

Chromosomal translocations are important drivers of haematological malignancies whereby proto-oncogenes are activated by juxtaposition with super-enhancers, often called super-enhancer hijacking. We analysed the epigenomic consequences of rearrangements between the enhancers of the immunoglobulin heavy chain locus (IGH) and proto-oncogene CCND1 that are common in B-cell malignancies. By integrating BLUEPRINT epigenomic data with DNA breakpoint detection, we characterised the normal chromatin landscape of the human IGH locus and its dynamics after pathological genomic rearrangement. We detected an H3K4me3 broad domain (BD) within the IGH locus of healthy B-cells that was absent in samples with IGH-CCND1 translocations. The appearance of H3K4me3-BD over CCND1 in the latter was associated with overexpression and extensive chromatin accessibility of this locus. We observed similar cancer-specific H3K4me3-BDs associated with super-enhancer hijacking of other common oncogenes in B-cell (MAF, MYC and FGFR3) and in T-cell malignancies (LMO2, TLX3 and TAL1). Our analysis suggests that H3K4me3-BDs are created by super-enhancers and supports the new concept of epigenomic translocation, where the relocation of H3K4me3-BDs accompanies the translocation of super-enhancers.

Detecting how to clinically target the leukaemia microenvironment has remained a substantial hindrance in drug discovery and drug development. To address this clinical challenge, we have developed a human pluripotent stem cell-engineered co-culture system to support the ex vivo propagation of patient-derived leukaemia cells and to explore actionable niche-mediated blood cancer biology. Here we show that both messenchymal and vascular niche cell types impact malignant proliferation, dormancy and treatment resistance. Furthermore, both the niche cell types supported blast proliferation and conferred dexamethasone resistance onto patient-derived leukaemia cells. While vascular cells protected only quiescent blasts against dexamethasone, mesenchymal cells protected both proliferating and dormant blasts. Growth support and treatment protection was dependent on direct cell-cell interaction and was mediated by N-cadherin (CDH2). We show that CDH2 antagonist ADH-1, a compound with a proven low toxicity profile in adult solid tumour Phase l trials showed high in vivo efficacy in a highly aggressive and incurable leukaemia patient-derived xenograft model. Furthermore, we observed superior in vivo efficacy of ADH-1/Dexamethasone combination compared with single agent Dexamethasone therapy. These findings provide a proof-of-concept starting point to begin investigations into novel and potentially safe anti-cancer therapeutics that target actionable niche-mediated cancer cell dependencies in haematological malignancies.