Abstract 3307: Improved survival in AML by in vivo drug targeting of conserved regulatory pathways in phenotypically distinct tumor-initiating compartments

Abstract

Abstract Increasing evidence suggests tumors are maintained by cancer stem cells, however their nature remains controversial. In a HoxA9-Meis1 (H9M) driven model of acute myeloid leukemia (AML), we found that tumor-initiating activity existed in three, immunophenotypically distinct compartments, corresponding to disparate lineages on the normal hematopoietic hierarchy–stem/progenitor cells (Lin−kit+), and committed progenitors of the myeloid (Gr1+kit+) and lymphoid lineages (Lym+kit+). Each compartment clonally recapitulated the original range of tumor cell immunophenotypes in vivo, including cells with a less-differentiated immunophenotype. These distinct populations largely shared signaling networks, and in vivo pharmacologic targeting of shared pathways (DNA methyltransferase and MEK phosphorylation) significantly increased survival. Collectively, these data show that H9M AML is organized as an atypical hierarchy that defies the strict lineage marker boundaries and unidirectional differentiation of normal hematopoiesis. Moreover, in some malignancies, tumor-initiation ability (or “cancer-stemness”) can represent a targetable, cellular state that can exithat exists independently of distinct immunophenotypic definition. 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 3307. doi:1538-7445.AM2012-3307