TY - JOUR
T1 - Focal adhesion kinase as a potential target inAML & MDS
AU - Carter, Bing Z.
AU - Mak, Po Yee
AU - Wang, Xiangmeng
AU - Yang, Hui
AU - Garcia-Manero, Guillermo
AU - Mak, Duncan H.
AU - Mu, Hong
AU - Ruvolo, Vivian R.
AU - Qiu, Yihua
AU - Coombes, Kevin
AU - Zhang, Nianxiang
AU - Ragon, Brittany
AU - Tweaver, David
AU - Pachter, Jonathan A.
AU - Kornblau, Steven
AU - Andreeff, Michael
N1 - Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/6
Y1 - 2017/6
N2 - Although overexpression/activation of focal adhesion kinase (FAK) is widely known in solid tumors to control cell growth, survival, invasion, metastasis, gene expression, and stem cell selfrenewal, its expression and function in myeloid leukemia are not well investigated. Using reverse-phase protein arrays in large cohorts of newly diagnosed acute myeloid leukemia (AML) and myeloid dysplastic syndrome (MDS) samples, we found that high FAK expression was associated with unfavorable cytogenetics (P= 2 × 10-4) and relapse (P = 0.02) in AML. FAK expression was significantly lower in patients with FLT3-ITD (P=0.0024) or RAS (P = 0.05) mutations and strongly correlated with p-SRC and integrinb3 levels. FAK protein levels were significantly higher in CD34 (P = 5.42 × 10-20) and CD34+CD38- MDS (P = 7.62 × 10-9) cells compared with normal CD34 cells. MDS patients with higher FAK in CD34 cells tended to have better overall survival (P = 0.05). FAK expression was significantly higher in MDS patients who later transformed to compared with those who did not transform to AML and in AML patients who transformed fromMDScompared with those with de novo AML. Coculture with mesenchymal stromal cells (MSC) increased FAK expression in AML cells. Inhibition of FAK decreased MSC-mediated adhesion/ migration and viability of AML cells and prolonged survival in an AML xenograft murine model. Our results suggest that FAK regulates leukemia-stromal interactions and supports leukemia cell survival; hence, FAK is a potential therapeutic target in myeloid leukemia.
AB - Although overexpression/activation of focal adhesion kinase (FAK) is widely known in solid tumors to control cell growth, survival, invasion, metastasis, gene expression, and stem cell selfrenewal, its expression and function in myeloid leukemia are not well investigated. Using reverse-phase protein arrays in large cohorts of newly diagnosed acute myeloid leukemia (AML) and myeloid dysplastic syndrome (MDS) samples, we found that high FAK expression was associated with unfavorable cytogenetics (P= 2 × 10-4) and relapse (P = 0.02) in AML. FAK expression was significantly lower in patients with FLT3-ITD (P=0.0024) or RAS (P = 0.05) mutations and strongly correlated with p-SRC and integrinb3 levels. FAK protein levels were significantly higher in CD34 (P = 5.42 × 10-20) and CD34+CD38- MDS (P = 7.62 × 10-9) cells compared with normal CD34 cells. MDS patients with higher FAK in CD34 cells tended to have better overall survival (P = 0.05). FAK expression was significantly higher in MDS patients who later transformed to compared with those who did not transform to AML and in AML patients who transformed fromMDScompared with those with de novo AML. Coculture with mesenchymal stromal cells (MSC) increased FAK expression in AML cells. Inhibition of FAK decreased MSC-mediated adhesion/ migration and viability of AML cells and prolonged survival in an AML xenograft murine model. Our results suggest that FAK regulates leukemia-stromal interactions and supports leukemia cell survival; hence, FAK is a potential therapeutic target in myeloid leukemia.
UR - http://www.scopus.com/inward/record.url?scp=85020796961&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-16-0719
DO - 10.1158/1535-7163.MCT-16-0719
M3 - Article
C2 - 28270436
AN - SCOPUS:85020796961
SN - 1535-7163
VL - 16
SP - 1133
EP - 1144
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 6
ER -