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A study of the genetic basis of evation by Acute Myeloid Leukaemia of Graft vs Leukaemia effects after allogeneic bone marrow transplantation

Acute myeloid leukaemia (AML) is an aggressive and molecularly diverse disease with a poor overall survival of 20-25%. With an annual incidence of 2.9 per 100,000, AML is currently the commonest myeloid malignancy in Europe, yet the two main therapeutic options for this disease, anthracyclines and purine analogues, have remained unchanged for over 20 years. Currently patients are stratified at diagnosis according to a series of clinicopathological parameters (e.g. age, white cell count and presence/absence of previous clonal haematological disease) and molecular markers (e.g. chromosomal translocations/deletions, aneuploidy and mutations in genes such as FLT3 and NPM1). Patients with adverse prognostic features, whose prognosis is particularly poor (e.g. <15% long-term survival) are offered treatment with allogeneic bone marrow transplantation (allo-BMT) if a sibling or unrelated donor is available. This can significantly improve survival (e.g. up to 40% long-term survival in some contexts), albeit at the expense of significant toxicity and transplant-related mortality (TRM). Allo-BMT is thought to work in part by allowing the delivery of large doses of chemotherapy followed by haemopoietic "rescue" with donor haemopoietic stem cells (haemopoietic failure would otherwise ensue). However, potentially the most potent effect of allo-BMT is the cytotoxic effect of donor lymphocytes against AML blasts, a phenomenon known as graft-vs-leukaemia (GVL) effect. Increasingly, transplants using reduced chemotherapy intensity (mini-allografts) are being used that partially circumvent the toxicity from chemotherapy and rely on GVL to effect cure. Nevertheless, AML relapse after allo-BMT still occurs at a significant rate of up to 80% depending on the type of transplant. There is accumulating evidence that genetic events in residual leukaemic cells enable them to evade immunodetection and therefore survive the GVL effect and expand to cause relapse. The most striking example of this is the loss of HLA antigens after transplants in which donor and recipient are not fully HLA-matched. In these cases, the leukaemia "deletes" the genomic region containing the disparate HLA antigen which was preferentially targeted as "foreign" by the GVL effect. However, the genetic basis of immune evasion in the majority of transplants, which are fully HLA matched, is not known. One possibility is that loss of genes coding for antigens outside the HLA locus but which are also targets of GVL may operate, alternatively genetic events that affect processes downstream of immunological cytotoxicity may be responsible. The identification of genetic events that mediate immune evasion would not only facilitate the understanding of this process but can help plan therapeutic interventions that improve the outcomes of allogeneic transplantation for AML and other disorders. We intend to study this by conducting exome sequencing on 6 cases of AMLs from patients that attend my clinic at Addenbrooke's hospital and have relapsed after allogeneic transplantation. Samples from AML diagnosis, remission/normal and AML relapse (total n=18) will be studied to identify somatic mutations in the primary AML and those acquired by the relapsed clone. The 18 samples will also be studied by array CGH to detect regions of genomic amplification or deletion.

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Studies are experimental investigations of a particular phenomenon, e.g., case-control studies on a particular trait or cancer research projects reporting matching cancer normal genomes from patients.

Study ID Study Title Study Type
EGAS00001000145 Other

This table displays only public information pertaining to the files in the dataset. If you wish to access this dataset, please submit a request. If you already have access to these data files, please consult the download documentation.

ID File Type Size Located in
EGAF00000104212 bam 4.3 GB
EGAF00000104213 bam 4.5 GB
EGAF00000111965 bam 4.3 GB
EGAF00000111966 bam 4.6 GB
EGAF00000111967 bam 4.0 GB
EGAF00000111968 bam 4.0 GB
EGAF00000111969 bam 4.1 GB
EGAF00000111970 bam 4.3 GB
EGAF00000111971 bam 4.7 GB
EGAF00000111972 bam 4.0 GB
EGAF00000111973 bam 4.2 GB
EGAF00000111974 bam 4.2 GB
EGAF00000111975 bam 4.3 GB
EGAF00000111976 bam 4.0 GB
EGAF00000111977 bam 4.4 GB
EGAF00000111978 bam 4.6 GB
EGAF00000111979 bam 4.8 GB
EGAF00000111980 bam 5.0 GB
EGAF00000111981 bam 5.3 GB
EGAF00000111982 bam 4.6 GB
EGAF00000111983 bam 4.6 GB
EGAF00000111984 bam 4.7 GB
EGAF00000111985 bam 4.9 GB
EGAF00000111986 bam 5.5 GB
EGAF00000111987 bam 4.6 GB
EGAF00000111988 bam 4.9 GB
EGAF00000111989 bam 5.1 GB
EGAF00000111990 bam 4.5 GB
EGAF00000111991 bam 4.5 GB
EGAF00000111992 bam 4.6 GB
EGAF00000111993 bam 4.8 GB
EGAF00000111994 bam 5.3 GB
EGAF00000111995 bam 4.5 GB
EGAF00000111996 bam 4.8 GB
EGAF00000111997 bam 4.7 GB
EGAF00000111998 bam 4.7 GB
EGAF00000111999 bam 4.8 GB
EGAF00000112000 bam 4.5 GB
EGAF00000112001 bam 5.0 GB
EGAF00000112002 bam 5.2 GB
EGAF00000112003 bam 5.4 GB
EGAF00000112004 bam 4.5 GB
EGAF00000112005 bam 4.4 GB
EGAF00000112006 bam 4.4 GB
EGAF00000112007 bam 4.2 GB
EGAF00000112008 bam 4.7 GB
EGAF00000112009 bam 4.9 GB
EGAF00000112963 bam 5.1 GB
EGAF00000112965 bam 9.9 GB
EGAF00000112966 bam 10.4 GB
EGAF00000112967 bam 11.2 GB
EGAF00000112968 bam 27.3 GB
EGAF00000120070 bam 12.7 GB
EGAF00000120071 bam 12.5 GB
EGAF00000166048 bam 8.9 GB
EGAF00000166049 bam 9.2 GB
EGAF00000166050 bam 9.2 GB
EGAF00000166051 bam 11.9 GB
EGAF00000166052 bam 12.7 GB
59 Files (357.6 GB)