Fas-associated phosphatase 1 mediates Fas resistance in myeloid progenitor cells expressing the Bcr-abl oncogene.

The interferon consensus sequence binding protein (Icsbp) is a transcription factor that influences multiple aspects of myelopoiesis. Expression of Icsbp is decreased in the bone marrow of human subjects with chronic myeloid leukemia (CML), and studies in murine models suggest that Icsbp functions as an anti-oncogene for CML. We previously identified a set of Icsbp target genes that may contribute to this anti-oncogene effect. The set includes PTPN13, the gene encoding Fas-associated phosphatase 1 (Fap1, a Fas antagonist). We previously demonstrated that myeloid progenitor cells from Icsbp-knockout mice exhibit Fap1-dependent Fas resistance. In the present study, we determined that the Fas resistance of Bcr-abl+cells is Icsbp- and Fap1-dependent. We also found that treatment of Bcr-abl bone marrow cells with a Fap1-blocking peptide prevents in vitro selection of a tyrosine kinase inhibitor (TKI)-resistant population. Therefore, these results have implications for therapeutic targeting of the Fas-resistant leukemia stem cell population and addressing TKI resistance in CML.