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Leukemia propagating cells rebuild an evolving niche in response to therapy

ABSTRACT: Residence of cancer-propagating cells (CPCs) within preferential microenvironmental niches has a major part in evading therapy. However, the nature of niches involved and the mechanisms protecting CPCs remain largely unknown. We addressed these issues in mouse transplantation models of acute lymphoblastic leukemia (ALL). When the engrafted leukemic cells substantially damaged adjacent vascular structures and endosteal linings in the bone marrow (BM), after chemotherapy small foci of CPCs were retained, surrounded by sheaths of supporting cells that comprise a novel niche. We investigated patients’ BM biopsies and found evidence of a similar process in patients receiving induction-therapy. The efficacy of chemotherapy was enhanced by interfering with the niche formation or niche-CPC interaction. We therefore identified a therapy-induced niche that protects CPCs. We used microarrays to compare the gene expression profile of ALL cell line (Nalm-6) from model (A0D) mice and rediduel cells from Ara-C treatment for 2 days (A2D) mice.

ORGANISM(S): Homo sapiens

PROVIDER: GSE56273 | GEO | 2014/04/21

SECONDARY ACCESSION(S): PRJNA242807

REPOSITORIES: GEO

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leukemia propagating cells rebuild an evolving niche in response to therapy

Project description:Residence of cancer-propagating cells (CPCs) within preferential microenvironmental niches has a major part in evading therapy. However, the nature of niches involved and the mechanisms protecting CPCs remain largely unknown. We addressed these issues in mouse transplantation models of acute lymphoblastic leukemia (ALL). When the engrafted leukemic cells substantially damaged adjacent vascular structures and endosteal linings in the bone marrow (BM), after chemotherapy small foci of CPCs were retained, surrounded by sheaths of supporting cells that comprise a novel niche. We investigated patients’ BM biopsies and found evidence of a similar process in patients receiving induction-therapy. The efficacy of chemotherapy was enhanced by interfering with the niche formation or niche-CPC interaction. We therefore identified a therapy-induced niche that protects CPCs. We used microarrays to compare the gene expression profile of ALL cell line (Nalm-6) from model (A0D) mice and rediduel cells from Ara-C treatment for 2 days (A2D) mice. Engrafted NALM-6-GFP+ cells from A0D mice and residual cells from A2D mice were flow sorted. Total RNA was isolated using RNeasy micro kit (Qiagen). Biotinylated cRNA was hybridized using HGU133Plus 2.0 GeneChip arrays (Affymetrix).

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