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Phosphoproteomic profiling of Acute Myeloid Leukaemia

ABSTRACT: Acute Myeloid Leukaemia (AML) carries a 5 year survival rate of just 24%. Toxic chemotherapy regimens remain the backbone of standard of care for AML. The FLT3 tyrosine kinase is a recognised AML oncogene, with FLT3 activating mutations occurring in approximately one third of all AML patients. However, therapeutic targeting of FLT3 has proven difficult as monotherapy, with the development of drug resistance and relapse. Characterisation of the signalling pathways regulated by mutant FLT3 is required to identify better therapeutic strategies.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Dr. Matt Dun Nikki Verrills

PROVIDER: MSV000084730 | MassIVE | Fri Dec 20 01:35:00 GMT 2019

SECONDARY ACCESSION(S): PXD016860

REPOSITORIES: MassIVE

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Project description:The frequent occurrence of persistent or relapsed disease following induction chemotherapy in AML necessitates a better understanding of the clonal relationship of AML in various disease phases. In this study, we employed SNP 6.0 array-based genomic profiling of acquired copy number aberrations (aCNA) and copy neutral LOH (cnLOH) together with sequence analysis of recurrently mutated genes to characterize paired AML genomes. We analyzed 28 AML sample pairs from patients that achieved complete remission with chemotherapy and subsequently relapsed and 11 sample pairs from patients with persistent disease following induction chemotherapy. Through review of aCNA/cnLOH and gene mutation profiles in informative cases we demonstrate that relapsed AML invariably represents reemergence or evolution of a founder clone. Furthermore, all individual aCNA or cnLOH detected at presentation persisted at relapse indicating that this lesion type is proximally involved in AML evolution. Analysis of informative paired persistent AML disease samples uncovered cases with two coexisting dominant clones of which at least one was chemotherapy sensitive and one resistant, respectively. These data support the conclusion that incomplete eradication of AML founder clones rather than stochastic emergence of fully unrelated novel clones underlies AML relapse and persistence with direct implications for clinical AML research This study is based on 39 patients with AML for which either paired enrollment or relapse samples or persistent disease samples were available. The patients were enrolled into this study at the University of Michigan Comprehensive Cancer Center. The study was approved by the University of Michigan Institutional Review Board (IRBMED #2004-1022) and written informed consent was obtained from all patients prior to enrollment. Genomic DNA was extracted from purified AML blasts and paired buccal cells. DNA thus obtained was hybridized to Affymetrix SNP 6.0 arrays. Note: There is no normal sample available for MIAML015.

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Phosphoproteomic profiling of Acute Myeloid Leukaemia

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