Focal adhesion kinase splice variants maintain primitive acute myeloid leukemia cells through altered Wnt signaling.
Focal adhesion kinase (FAK) activity contributes to many advanced cancer phenotypes, but little is known about its role in human acute myeloid leukemia (AML). Here, we show that FAK splice variants are abnormally expressed in the primitive leukemic cells of poor prognosis AML patients. In the CD34(+) 38(-) 123(+) long-term culture-initiating cell-enriched leukemic cells of these patients, FAK upregulates expression of Frizzled-4 and phosphorylates Pyk2 to enable the required association of Pyk2 with the Wnt5a/Frizzled-4/LRP5 endocytosis complex and downstream activation of β-catenin, thereby replacing the Wnt3a-controlled canonical pathway used by normal hematopoietic stem cells. Transduction of primitive normal human hematopoietic cells with FAK splice variants induces a marked increase in their clonogenic activity and signaling via the Wnt5a-controlled canonical pathway. Targeting FAK or β-catenin efficiently eradicates primitive leukemic cells in vitro suggesting that FAK could be a useful therapeutic target for improved treatment of poor prognosis AML cases.
Inserm U1043, CNRS U5282, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
Mathieu
M
Despeaux
Gaëtan
G
Chicanne
Evelyne
E
Rouer
Fabienne
F
De Toni-Costes
Jessica
J
Bertrand
Véronique
V
Mansat-De Mas
Nathalie
N
Vergnolle
Connie
C
Eaves
Bernard
B
Payrastre
Jean-Antoine
JA
Girault
Claire
C
Racaud-Sultan
D000368:Aged; D018952:Antigens, CD34 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051157:Frizzled Receptors / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D015398:Signal Transduction; D016019:Survival Analysis; D015533:Transcriptional Activation; D014162:Transfection; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
D018952:Antigens, CD34; C495270:CTNNB1 protein, human; D051157:Frizzled Receptors; D007527:Isoenzymes; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin; D051416:Focal Adhesion Protein-Tyrosine Kinases