The cell polarity PTK7 receptor acts as a modulator of the chemotherapeutic response in acute myeloid leukemia and impairs clinical outcome.
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.
Prebet
Thomas
T
INSERM U891, Centre de Recherche en Cancérologie de Marseille, Marseille, France.
Lhoumeau
Anne-Catherine
AC
Arnoulet
Christine
C
Aulas
Anaïs
A
Marchetto
Sylvie
S
Audebert
Stéphane
S
Puppo
Francesca
F
Chabannon
Christian
C
Sainty
Danielle
D
Santoni
Marie-Josée
MJ
Sebbagh
Michael
M
Summerour
Virginia
V
Huon
Yannick
Y
Shin
Won-Sik
WS
Lee
Seung-Taek
ST
Esterni
Benjamin
B
Vey
Norbert
N
Borg
Jean-Paul
JP
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
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D015815:Cell Adhesion Molecules; D017931:DNA Primers; C096905:PTK7 protein, human; D020794:Receptor Protein-Tyrosine Kinases