The biology of acute myeloid leukaemia (360G-Wellcome-205254_Z_16_Z)

£252,167

Mutations in epigenetic regulators play a pivotal role in leukaemia initiation. We propose to study the most commonly mutated epigenetic regulator in AML: the de novo DNA methyltransferase DNMT3a (25%). It is unclear how DNMT3a mutations subvert HSC, surprisingly in bulk studies differences in methylation do not correlate with differences in gene expression, but somehow DNMT3a mutated HSC have an advantage in xenografts and survive apparently successful chemotherapy in 80% of patients. Even if a persistent clone does not predict relapse rate these patients tend to have a poorer prognosis. DNMT3a mutations are also the most prevalent in individuals with "clonal haematopoiesis". To study DNMT3a mutated preleukaemia we will use a mouse model where the most common DNMT3a mutation (R882H) and an RFP are under the control of the Mx1-cre promoter. By titrating the dose of pIpC we will generate a chimeric mouse where only ~ 20% of cells express the mutant allele. We will study clonal dynamics after challenging HSC homeostasis (through lineage tracing of the RFP) and document alterations in gene expression at the single cell level at baseline and after perturbing HSC using state-of-the-art technology (Polaris system). We will then corroborate our findings in human DNMT3aR882 preleukaemia.

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Grant Details

Amount Awarded 252167
Applicant Surname Marando
Approval Committee Internal Decision Panel
Award Date 2016-09-30T00:00:00+00:00
Financial Year 2015/16
Grant Programme: Title PhD Training Fellowship for Clinicians
Internal ID 205254/Z/16/Z
Lead Applicant Dr Ludovica Marando
Partnership Value 252167
Planned Dates: End Date 2022-02-28T00:00:00+00:00
Planned Dates: Start Date 2016-11-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region East of England