Control of Lineage Commitment in Acute Leukaemia

Introduction: Whilst translocations involving MLL (11q23) result in a spectrum of acute leukaemias, MLL/AF4 is specifically associated with B ALL. We describe an ALL to AML lineage switch patient with identical t(4;11) translocations. We have characterised this case in order to study the control of lineage commitment and the haematopoietic origin of the leukaemia.

Methods: RNAseq and DNase hypersensitivity analysis showed genomic fingerprinting consistent with a switch from lymphoid to myeloid lineage. Exome and RNA seq identified 13 novel deleterious mutations in the AML, all of which belong to the top 25% expressed genes. Affected genes included a number of epigenetic modifiers.

Results: We also sorted both ALL and AML and have demonstrated the presence of MLL/AF4 in multipotential progenitors (MPP) onwards but not the HSC. This finding is in keeping with the lack of IgH rearrangement seen in the AML, predicting a cell of origin prior to lymphoid commitment. In this most primitive population, the AML carries mutations in CHD4 and PHF3 suggesting their importance in lineage commitment.

Conclusion: We suggest that the ALL and AML share a common pre-leukaemic cell of origin that may have arisen within the MPP compartment.