Founding clones and evolving subclones: Insights in acute myeloid leukaemia from next-generation sequencing


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John Welch
Washington University, St Louis, USA

Abstract

To better understand the molecular origin and evolution of AML-associated mutations, we sequenced the genomes of 12 cases of M3 AML (which is initiated by PML-RARA), 12 cases of normal karyotype FAB M1 AML (where the initiating mutations are less well understood), and the exomes of hematopoietic stem/progenitor cells (HSPCs) from 7 healthy people. Each M1 and M3 genome contained only a few recurrently mutated genes (average: 3.4 per genome for M1, and 2.2 for M3, including PML-RARA), a small number of genic mutations (6-22 for M1, and 3-24 for M3, including PML-RARA), and hundreds of total mutations (134-651 for M1, and 116-651 for M3) that were present in most cells; the total number of mutations per genome correlated to the patient's age. Within half of all AML cases, mutational clusters identified 1 or more subclones, in addition to a founding clone. Further, we found that normal HSPCs also contain mutations that mirror those of AML cases, both in the rate of mutation acquisition (~0.1 - 0.2 exome mutations acquired per HSPC per year), and in the type of mutations present (predominantly C>T/A>G transitions). These data suggest that most AML-associated mutations are random events that occurred in an HSPC prior to the initiating event; the mutational history of that HSPC is "captured" by this initiation event and persists as the clone expands. In many cases, only one or two additional, cooperating mutations are required for AML. Finally, cells within the founding clone may continue to acquire both random and pathogenic mutations, resulting in subclonal evolution that may contribute to disease progression or relapse.