GSE75086
Cellular and Molecular Targeting of Recurrence in Acute Myeloid Leukemia
While disease recurrence remains the outstanding clinical challenge in acute myeloid leukemia (AML), the basis of relapse remains poorly characterized and thereby preventing effective therapeutic targeting. We performed gene expression analysis of human AML patient samples in addition to in vitro and in vivo assays of leukemic cell survival and self-renewal using xenograft modeling. These molecular and functional analyses afforded the identification of unique target genes that support recurrence. Preclinical modeling using these novel targets provided proof-of-principle for combination therapies towards more effective and durable suppression of AML regrowth. Overall design: AML samples were obtained from patients belonging to intermediate- and high-risk prognostic groups and healthy hematopoietic cells were obtained from mobilized peripheral blood (MPB) or bone marrow (BM) of healthy donors. Xenotransplant assays were performed by intravenous injection of primary human samples into sub-lethaly irradiated immunodefcient mice. RNA was purified from healthy MNCs, FACS-purified patient leukemic blasts (based on side scatter and CD45 intensity) and from xenografts purified from the recipient mouse BM. Transcriptional profiles were compared after AraC-based chemotherapy at post-induction or relapse, relative to untreated diagnostic samples in human patients. AraC cytoredutive therapy was simulated In xenografts assays and gene expression was analyzed post induction or at relapse compared to saline-treated matched xenografts as control.