TY - JOUR
T1 - Harnessing gene expression profiles for the identification of ex vivo drug response genes in pediatric acute myeloid leukemia
AU - Cucchi, David G.J.
AU - Bachas, Costa
AU - van den Heuvel-Eibrink, Marry M.
AU - Arentsen-Peters, Susan T.C.J.M.
AU - Kwidama, Zinia J.
AU - Schuurhuis, Gerrit J.
AU - Assaraf, Yehuda G.
AU - de Haas, Valérie
AU - Kaspers, Gertjan J.L.
AU - Cloos, Jacqueline
PY - 2020/5
Y1 - 2020/5
N2 - Novel treatment strategies are of paramount importance to improve clinical outcomes in pediatric AML. Since chemotherapy is likely to remain the cornerstone of curative treatment of AML, insights in the molecular mechanisms that determine its cytotoxic effects could aid further treatment optimization. To assess which genes and pathways are implicated in tumor drug resistance, we correlated ex vivo drug response data to genome-wide gene expression profiles of 73 primary pediatric AML samples obtained at initial diagnosis. Ex vivo response of primary AML blasts towards cytarabine (Ara C), daunorubicin (DNR), etoposide (VP16), and cladribine (2-CdA) was associated with the expression of 101, 345, 206, and 599 genes, respectively (p < 0.001, FDR 0.004–0.416). Microarray based expression of multiple genes was technically validated using qRT-PCR for a selection of genes. Moreover, expression levels of BRE, HIF1A, and CLEC7A were confirmed to be significantly (p < 0.05) associated with ex vivo drug response in an independent set of 48 primary pediatric AML patients. We present unique data that addresses transcriptomic analyses of the mechanisms underlying ex vivo drug response of primary tumor samples. Our data suggest that distinct gene expression profiles are associated with ex vivo drug response, and may confer a priori drug resistance in leukemic cells. The described associations represent a fundament for the development of interventions to overcome drug resistance in AML, and maximize the benefits of current chemotherapy for sensitive patients.
AB - Novel treatment strategies are of paramount importance to improve clinical outcomes in pediatric AML. Since chemotherapy is likely to remain the cornerstone of curative treatment of AML, insights in the molecular mechanisms that determine its cytotoxic effects could aid further treatment optimization. To assess which genes and pathways are implicated in tumor drug resistance, we correlated ex vivo drug response data to genome-wide gene expression profiles of 73 primary pediatric AML samples obtained at initial diagnosis. Ex vivo response of primary AML blasts towards cytarabine (Ara C), daunorubicin (DNR), etoposide (VP16), and cladribine (2-CdA) was associated with the expression of 101, 345, 206, and 599 genes, respectively (p < 0.001, FDR 0.004–0.416). Microarray based expression of multiple genes was technically validated using qRT-PCR for a selection of genes. Moreover, expression levels of BRE, HIF1A, and CLEC7A were confirmed to be significantly (p < 0.05) associated with ex vivo drug response in an independent set of 48 primary pediatric AML patients. We present unique data that addresses transcriptomic analyses of the mechanisms underlying ex vivo drug response of primary tumor samples. Our data suggest that distinct gene expression profiles are associated with ex vivo drug response, and may confer a priori drug resistance in leukemic cells. The described associations represent a fundament for the development of interventions to overcome drug resistance in AML, and maximize the benefits of current chemotherapy for sensitive patients.
KW - Chemotherapy
KW - Cladribine
KW - Cytarabine
KW - Daunorubicin
KW - Drug resistance
KW - Drug response
KW - Etoposide
KW - Gene expression
KW - Pediatric acute myeloid leukemia
UR - http://www.scopus.com/inward/record.url?scp=85085090923&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cancers12051247
DO - https://doi.org/10.3390/cancers12051247
M3 - Article
C2 - 32429253
SN - 2072-6694
VL - 12
JO - Cancers
JF - Cancers
IS - 5
M1 - 1247
ER -