Abstract 1748: Organ-specific epigenetic reprogramming of leukemia cells: Clues to chemoresistance

Isabel Cunningham; Diane Hamele-Bena; Audrey Papp; Yan Guo; Antony B Holmes; Yu Shyr; Rory A Fisher

doi:10.1158/1538-7445.AM2017-1748

We previously reported our observation that tumors composed of leukemic cells found in breast mimic solid breast cancers in gross and histologic appearance (single-filing of cells and distinctive keloid-like fibrosis), invasiveness, metastatic pathway, and high mortality. They are resistant to anti-leukemia drugs; only 4% treated without excision lived 4 years but survivals over 20 yrs resulted when tumor and its microenvironment were excised. The incidence of occult leukemic tumors, still unknown as scans are not yet routine, was estimated near 20% in 1970s autopsy studies. We hypothesized there may be similarly altered genes in leukemic and epithelial breast tumors directing clinical behavior and resistance that could provide targets for curative treatment. We performed RNA sequencing on 11 FFPE breast tumors from annotated AML cases, all IHC-negative for hormones and E-cadherin, compared to normal breast samples. Differential expression analysis identified 3647 genes that were significantly downregulated (adjusted p < 0.05 and log2 fold change < -2). Among the 100 genes downregulated 8-10 fold in leukemic breast, FOXA1, CA12, CXCL14, SFRP1, SFRP4, DCN, LUM, PHLDA1, NTN4, GABRP, TAGLN, AZGP1, and ARRDC3 have been associated with poor prognosis in breast cancer, mainly triple-negative (TNBC)/basal types. Compared to TNBC cases in the TCGA database, 851 genes were similarly deregulated; significantly enriched KEGG pathways include neuroactive ligand-receptor interaction, focal adhesion, ECM-receptor interaction, and regulation of lipolysis in adipocytes. A role for altered stroma is suggested as many of the similarly downregulated genes were reported in dissected breast cancer stroma and silenced SFRP1 and CXCL14 were found in keloid fibroblasts. Silencing of SFRP1 and E-cadherin in AML marrows was reported in 30-50% and each was correlated with poor survival. Reversal of SFRP1 silencing has been achieved by epigenetic-modifying drugs in cancers and keloid fibroblasts. We validated loss of SFRP1 and RGS6 in leukemic breasts by RT-PCR. Loss of RGS6 in breast and other cancers promotes doxorubicin resistance and DNMT1 upregulation leading to silencing of tumor suppressor genes. These data open a new view of resistance of AML cells to marrow-directed drugs through interaction with aberrant microenvironment. Solid tumors of epithelial and leukemic cells may share unrecognized treatable targets. Adding drugs directed at tumor, including available epigenetic-modifying agents, to marrow-effective protocols, may finally decrease the persistently high rate of AML treatment failure.

Abstract 1748: Organ-specific epigenetic reprogramming of leukemia cells: Clues to chemoresistance

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