RT Journal Article
SR Electronic
T1 Genomics of primary chemoresistance and remission induction failure in pediatric and adult acute myeloid leukemia
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 051177
DO 10.1101/051177
A1 Fiona C. Brown
A1 Paolo Cifani
A1 Esther Drill
A1 Jie He
A1 Eric Still
A1 Shan Zhong
A1 Sohail Balasubramanian
A1 Dean Pavlick
A1 Bahar Yilmazel
A1 Kristina M. Knapp
A1 Todd A. Alonzo
A1 Soheil Meshinchi
A1 Richard M. Stone
A1 Steven M. Kornblau
A1 Guido Marcucci
A1 Alan S. Gamis
A1 John C. Byrd
A1 Mithat Gonen
A1 Ross L. Levine
A1 Alex Kentsis
YR 2016
UL http://biorxiv.org/content/early/2016/04/30/051177.abstract
AB Despite intense efforts, the cure rates of children and adults with AML remain unsatisfactory in large part due to resistance to chemotherapy. Whilst cytogenetic risk stratification proved valuable in identifying causes of therapy failure and disease relapse, cytogenetically normal AML remains the most prevalent disease type, with significant heterogeneity of clinical outcomes, including primary chemoresistance. Using targeted sequencing of 670 genes recurrently mutated in hematologic malignancies, we investigated the genetic basis of primary chemotherapy resistance and remission induction failure of 107 primary cases obtained at diagnosis from children and adults with cytogenetically normal AML. Comparative analysis revealed mutations of SETBP1, ASXL1 and RELN to be significantly enriched at diagnosis in primary induction failure as compared to remission cases. In addition, this analysis revealed novel genomic alterations not previously described in AML, as well as distinct genes that are significantly overexpressed in therapy resistant AML. However, identified gene mutations were sufficient to explain only a minority of cases of primary induction failure. Thus, additional genetic or molecular mechanisms must cause primary chemoresistance in pediatric and adult acute myeloid leukemias.Key PointsTargeted gene sequencing of 670 genes in adult and pediatric AMLProfiling of 107 primary AML samples identifies new genomic alterations for primary chemoresistance