Abstract SY35-01: Clonal evolution of pre-leukemic hematopoietic stem cells precedes human acute myeloid leukemia

Abstract

Abstract Acute myeloid leukemia (AML) is an aggressive malignancy of hematopoietic progenitors with poor clinical outcomes. Despite the power of next-generation genome sequencing to describe AML genomes and to identify recurrent mutations, our fundamental understanding of both the genomics of leukemogenesis and the genetic heterogeneity within the precursor cells is incomplete. Founding mutations in the majority of AML cases are largely unknown because pre-leukemic cells are clinically silent and are outcompeted by their malignant descendants. Our limited knowledge of founding mutations comes from infrequent cases of AML arising secondary to antecedent clonal bone marrow disorders or rare instances of inherited syndromes, but this does not include the large majority of de novo AML cases. Recently, advances in AML stem cell biology have enabled the prospective separation of residual hematopoietic stem cells (HSC) from AML cells. We previously showed that residual HSC contain clonal antecedents of AML in patients in long-term remission post-therapy, and have proposed a model in which serial acquisition of mutations occurs in self-renewing HSC. Here, we investigated this model and the nature of founder mutations through the genomic analysis of de novo AML and patient-matched residual HSC. Using exome sequencing, we defined mutations present in individual AML genomes from cases harboring the FLT3-ITD mutation, and screened for these mutations in the residual HSC. We identified several mutations present in residual HSC retaining normal multilineage differentiation in vivo, including mutations in NPM1, TET2, and SMC1A, a newly identified recurrently mutated gene in AML. Finally, through single cell analysis, we determined that as we hypothesized, a clonal progression of multiple mutations occurs in HSC. These pre-leukemic HSC reveal the clonal evolution of AML genomes from founder mutations, suggest a potential mechanism contributing to relapse, and constitute a cellular reservoir that may need to be targeted for more durable remissions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY35-01. doi:1538-7445.AM2012-SY35-01