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Title: Control of lineage commitment in acute leukaemia
Authors: Tirtakusuma, Ricky Fong
Issue Date: 2018
Publisher: Newcastle University
Abstract: Acute leukaemia with the t(4;11) translocation is strongly associated with pro B-acute lymphoblastic phenotype. Here is described a lineage switch from acute lymphoblastic leukaemia (ALL) to acute myeloid leukaemia (AML) which carries identical t(4;11) breakpoints that provides insight into regulation of lineage commitment and the haematopoietic origin of leukaemia. Stable DNA microsatellite sequences argue against a therapy-related AML. Genome sequencing and RNAseq identified 12 novel and deleterious mutations unique to the AML. Immunoglobulin rearrangement analysis suggested the common cell of origin lied within a population prior to B cell differentiation. Sorting of haematopoietic stem/progenitor cell populations followed by multiplex PCR and next generation sequencing for the fusion and secondary mutations demonstrated the occurrence of the leukaemogenic MLL-AF4 fusion gene in cell populations as early as the multipotent progenitor, MPP, population in both ALL and AML. In this most primitive population, the AML carries mutations in chromatin modulating genes CHD4 and PHF3, suggesting their importance in lineage commitment. Knockdown CHD4 and PHF3 individually and in combination in the pro-B ALL t(4;11) SEM cell line resulted in ~3 fold higher expression of the myeloid cell surface marker CD33. Further analysis was performed using a recently described model of MLL-AF4 leukaemogenesis consisting of CD34+ cord blood cells transduced with a chimeric MLL-Af4 fusion gene. Knockdown of CHD4 and PHF3 resulted in loss of lymphoid differentiation potential in vitro. Analysis of different PHF3 splice variants revealed that only mutation-carrying PHF3 variants increased CD33 on SEM cells and that a balance between PHF3 variants was required for the lineage fidelity. This study suggests that the ALL and AML share a common primitive cell of origin and that mutations in CHD4 and PHF3 shift the lymphoid phenotype towards a myeloid lineage leukaemia.
Description: PhD Thesis
Appears in Collections:Northern Institute for Cancer Research

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