title: 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.
authors.affiliation: INSERM U891, Centre de Recherche en Cancérologie de Marseille, Marseille, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Prebet
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Lhoumeau
authors.forename: Christine
authors.initials: C
authors.lastname: Arnoulet
authors.forename: Anaïs
authors.initials: A
authors.lastname: Aulas
authors.forename: Sylvie
authors.initials: S
authors.lastname: Marchetto
authors.forename: Stéphane
authors.initials: S
authors.lastname: Audebert
authors.forename: Francesca
authors.initials: F
authors.lastname: Puppo
authors.forename: Christian
authors.initials: C
authors.lastname: Chabannon
authors.forename: Danielle
authors.initials: D
authors.lastname: Sainty
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Santoni
authors.forename: Michael
authors.initials: M
authors.lastname: Sebbagh
authors.forename: Virginia
authors.initials: V
authors.lastname: Summerour
authors.forename: Yannick
authors.initials: Y
authors.lastname: Huon
authors.forename: Won-Sik
authors.initials: WS
authors.lastname: Shin
authors.forename: Seung-Taek
authors.initials: ST
authors.lastname: Lee
authors.forename: Benjamin
authors.initials: B
authors.lastname: Esterni
authors.forename: Norbert
authors.initials: N
authors.lastname: Vey
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Borg
mesh_terms: D018943:Anthracyclines / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D016764:Cell Polarity; D020732:Cytogenetic Analysis; D017931:DNA Primers / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D018922:HL-60 Cells; D006801:Humans; D016130:Immunophenotyping; D066298:In Vitro Techniques; D019169:Jurkat Cells; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome; D020298:U937 Cells
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D015815:Cell Adhesion Molecules; D017931:DNA Primers; C096905:PTK7 protein, human; D020794:Receptor Protein-Tyrosine Kinases