The cell polarity PTK7 receptor acts as a modulator of the chemotherapeutic response in acute myeloid leukemia and impairs clinical outcome

Abstract

The pseudo tyrosine kinase receptor 7 (PTK7) is an orphan tyrosine kinase receptor assigned to the planar cell polarity pathway. It plays a major role during embryogenesis and epithelial tissue organization. Here we found that PTK7 is also expressed in normal myeloid progenitors and CD34 ؉ CD38 ؊ bone marrow cells in humans. We performed an immunophenotyping screen on more than 300 patients treated for hematologic malignancies. We demonstrated that PTK7 is expressed in acute myeloid leukemia (AML) and is mostly assigned to granulocytic lineage differentiation. Patients with PTK7-positive AML are more resistant to anthracycline-based frontline therapy with a significantly reduced leukemia-free survival in a multivariate analysis model. In vitro, expression of PTK7 in cultured leukemia cells promotes cell migration, cell survival, and resistance to anthracycline-induced apoptosis. The intracellular region of PTK7 is required for these effects. Furthermore, we efficiently sensitized primary AML blasts to anthracycline-mediated cell death using a recombinant soluble PTK7-Fc protein. We conclude that PTK7 is a planar cell polarity component expressed in the myeloid progenitor compartment that conveys promigratory and antiapoptotic signals into the cell and that represents an independent prognosis factor of survival in patients treated with induction chemotherapy. (Blood. 2010;116(13):2315-2323)

Ptk7-Deficient Mice Have Decreased Hematopoietic Stem Cell Pools as a Result of Deregulated Proliferation and Migration

“…This observation confirms that our previous data obtained from human leukemia samples (27) can be linked with already-described functions of PTK7 in cell migration and in metastatic dissemination. Indeed, we (27) and other investigators (29,48,49) found that PTK7 expression on various cancer cells is linked with higher metastasis potential. Recently, we also described a poor prognosis of PTK7 expression in colon cancer cells linked with higher metastatic events (50).…”

“…Indeed, PTK7 is expressed at the cell surface of human hematopoietic progenitors and blast cells from patients with acute myeloid leukemia. Overexpression of the PCP protein leads to increased cell survival and cell migration of leukemic cells and confers a poor prognosis to patients independently of other risk factors (27). Similar conclusions were recently drawn from studies done in chronic lymphocytic leukemia in which a set of PCP proteins is upregulated (30).…”

“…We previously identified the cell polarity protein PTK7 as a novel tyrosine kinase receptor that is overexpressed in acute myeloid leukemia. High expression of PTK7 is correlated with poor prognosis and resistance to chemotherapeutic regimens (27). Recently, another study revealed that PTK7 is also upregulated in T acute lymphocytic leukemia (37).…”

“…TF1 cells were grown in IMDM supplemented with 5 ng/ml GM-CSF and supplemented with EPO (2 UI/ml) for erythroid differentiation. TF1 cells were infected by viral particles containing short hairpin RNA (shRNA) against PTK7, as previously described (27). A scramble nontargeting shRNA was used as a control.…”

“…PTK7 is a type I protein composed of seven Ig loops in its extracellular region, a transmembrane domain, and an intracellular region with a tyrosine kinase domain (17,18,22,23). Although PTK7 is catalytically inactive, the cytoplasmic domain containing the tyrosine kinase domain is mandatory for receptor function in vitro and in vivo (24)(25)(26)(27). Both extracellular and intracellular domains of PTK7 can be released from the plasma membrane following the sequential cleavage of the receptor by membrane type 1-matrix metalloproteinase/ADAM-17 and g-secretase, interfering with its PCP and promigratory activities (24,28,29).…”