The Cell Polarity PTK7 Receptor Is Expressed in Myeloid Cells and Acts as a Modulator of the Chemotherapeutic Response in AML Patients.

Abstract 1571

Poster Board I-596

The pseudo tyrosine kinase receptor 7 (PTK7) is an orphean tyrosine kinase receptor assigned to the planar cell polarity pathway (PCP). It has been recently described and plays a major role during embryogenesis and epithelial tissue organisation. To date there is no report in the litterature considering a potential implication in hematopoiesis. In silico and in vitro analysis found that PTK7 was also expressed in normal myeloid progenitors and CD34⁺ CD38^- bone marrow cells in humans. Preliminary results from our team showed that PTK7 was also expressed in various leukemic cell lines such Jurkat, TF-1 or KG-1a. We decided to perform a wide range multicolour immunophenotyping screen on patients with acute myeloid leukemia (AML) at diagnosis and to investigate the role of PTK7 in AML in vitro. More than 250 patient samples were evaluated and we demonstrated that PTK7 was largely expressed in AML as 72% of the samples were PTK7 positive. Its expression mostly correlates with granulocytic lineage differentiation. PTK7 expression was associated with a lower WBC count at diagnosis and a lower frequency of extramedullary disease whatever was FAB subtype. Interestingly, PTK7 expression was associated with some cytogenetic subgroups including CBF-AML and APL. There was no correlation with molecular subgroups (i.e. FLT3-ITD/NPM1/CEBPA status). Overall Survival and Relapse Free Survival were evaluated in non-APL patients treated with induction chemo (n=182). Patients with PTK7 positive AML are more resistant to anthracycline-based frontline therapy with a significantly reduced Relapse Free Survival in a multivariate analysis model integrating all pre treatment variables (2 year probability of RFS= 29% vs 66% for PTK7 negative patients, p= 0.003). Forrest plot analysis showed that the negative impact of PTK7 expression was the most significant in intermediate cytogenetic risk subgroup and when PTK7 was aberrantly expressed in M4-M5 FAB subtypes. There was no demonstrated impact on CR. In cultured cells, expression of PTK7 promotes leukemia cell migration, cell survival and resistance to anthracyclin-induced apoptosis. There was no effect of PTK7 expression on cell proliferation in tritiated thymidine assay. In the absence of known inhibitor of PTK7, we produced a soluble recombinant PTK7-Fc protein that efficiently competes for PTK7 functions in cell migration and survival assays in cell lines and primary AML samples. These data were confirmed using a shRNA strategy. We conclude that PTK7 is a PCP component expressed in the myeloid progenitor compartment that conveys promigratory and anti-apoptotic signal to leukemia cells. Its use as a potential biomarker or therapeutical target should be investigated.