2017 – EXPLOITING THE FOETAL ORIGIN OF MLL-AF4-DRIVEN ACUTE LYMPHOBLASTIC LEUKAEMIA

Abstract

Infant MLL-AF4-driven Acute Lymphoblastic Leukaemia (ALL) is a devastating disease with dismal prognosis which has not improved with the advances of medicine. The lack of progress towards successfully treating these patients has been attributed to a lack of understanding of the unique biology of this disease, particularly its prenatal origin. To better understand the prenatal origin of the disease, we performed multiple RNA sequencing experiments on foetal, neonatal and adult haematopoietic stem and progenitor cells (HSPCs) from human and mouse. With this approach we identified a conserved foetal transcriptional signature that was characterised by a prominent proliferative and oncogenic nature, suggesting that the foetal origin of the disease could be critical for the initiation of this aggressive leukaemia. Interestingly, multiple aspects of the foetal transcriptome persisted into the blasts derived from infant patients. By performing multiple comparisons, we obtained a list of 20 conserved genes that were highly expressed in the healthy foetal tissues and in the infant blasts whereas there was little expression in neonatal and adult HSPCs. Pharmacological and genetic targeting of these genes had a dramatic effect on the survival of SEM cells, a cell line derived from an infant/paediatric patient with MLL-AF4-driven ALL. Amongst the more attractive targets were genes PLK1, which is involved in cell division, and ELOVL1 which is required for the elongation of very long fatty acid chains. PLK1 inhibition of SEM cells with the FDA approved inhibitor Volasertib resulted in a dramatic decrease in the proliferation potential of these cells which lead to apoptosis. Similarly, genetic targeting of ELOVL1 with CrispR-Cas9 showed a tremendous decrease in the survival of SEM cells. To identify the mechanisms of action of ELOVL1 we performed a lipidomics experiment where it was shown that there was a dramatic decrease in lipids that are involved in the maintenance of cell membranes. As expression of ELOVL1 was very low in healthy bone marrow haematopoietic cells, it seems that this requirement is unique to the infant disease and therefore a novel therapeutic avenue of treating the infant patients. In summary, in this study we describe a novel approach that allowed us to identify the Achilles heel of infant MLL-AF4-driven ALL which its foetal origin.