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