Genomic characterisation of lineage switched MLL-rearranged leukemias

Unlike other MLL rearrangements, t(4;11) is strongly associated with ALL. Here we have characterised the lineage switch from ALL to AML which carry identical MLL breakpoint. Nine t(4;11) and one t(9;11) cases were defined by loss of B lymphoid and gain of myeloid antigens and/or unequivocal changed to myeloid morphology. Performed RNAseq and DNase-seq analyses revealed myeloid-like transcriptional reprogramming in relapse samples, as well as chromatin reorganisation associated with changed TFs occupation of lymphoid and myeloid genes on presentation and relapse, respectively. The fusion MLL/AF4 gene can be detected in the multipotent progenitor (MPP) cells in both presentation and relapse, indicating an early HSPC as a potential cell of origin. Notably, mutations in PHF3 and CHD4, correlated with epigenetics regulation, were also identified in the relapse MPP. Moreover, knockdown of these genes in SEM cells and CD34+ chimeric MLL/Af4 cells trigger a myeloid programme. Taken together, these data show that the strong lymphoid potential of MLL/AF4 depends on the CHD4 and PHF3, and that mutations in these epigenetic regulators direct the switch towards the myeloid lineage.