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. Disclosures No relevant conflicts of interest to declare.

Targeting Wnt signaling pseudokinases in hematological cancers

“…In hematological malignancies, varying levels of PTK7 were observed in AML, B-ALL, and T-ALL. 12,66,67 Approximately twothirds of AML blasts express PTK7 potentially making it a prognostic marker, and its expression has been associated with a bad prognosis and an increased early relapse rate. 12 Furthermore, PTK7 expression increases chemotherapeutic resistance to anthracycline-based drugs such as doxorubicin, a process that could be reversed by blocking PTK7 signaling with an Fc-PTK7 soluble protein.…”

“…12,66,67 Approximately twothirds of AML blasts express PTK7 potentially making it a prognostic marker, and its expression has been associated with a bad prognosis and an increased early relapse rate. 12 Furthermore, PTK7 expression increases chemotherapeutic resistance to anthracycline-based drugs such as doxorubicin, a process that could be reversed by blocking PTK7 signaling with an Fc-PTK7 soluble protein. 12 Altogether, these data provide evidence for a role for PTK7 in drug resistance and suggest that the use of PTK7 agonists or antagonists should be explored for therapeutic purposes in leukemia/cancer treatment.…”

“…1,[8][9][10] Interestingly, higher expression levels of these Wnt-binding receptor pseudokinases in different hematological cancers have prompted in depth studies of their oncogenic role in sustaining cancer cell survival and therapy resistance. [11][12][13][14] In recent years, significant progress has been made using preclinical and clinical models to demonstrate their potential in targeted therapies for cancer treatment, including hematological cancers, which are the focus of this review.…”

Tunable Multivalent Aptamer-Based DNA Nanostructures To Regulate Multiheteroreceptor-Mediated Tumor Recognition

“…A great challenge in tumor diagnosis and treatment is the lack of high specific markers . Although receptors like CD71, c-Met, PTK7 are reported to be overexpressed in many tumor cells, they also exist on some normal cells. − Given that the tumor cells might be better discriminated from normal cells through multiple markers, we installed two kinds of aptamers on the nanostructures to enhance the specific binding of tumors. As illustrated in Figure a, we prepared DNA nanostructures named di mvAp-DNPs or di mvAp-DNTs with two types of aptamers (array 3 or array 4).…”