Genomics of primary chemoresistance and remission induction failure in pediatric and adult acute myeloid leukemia

BioRxiv : the Preprint Server for Biology
Fiona C BrownAlex Kentsis


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 che...Continue Reading

Related Concepts

Hematologic Neoplasms
RELN gene
Adult Acute Myeloblastic Leukemia
Gene Mutation
Putative Polycomb Group Protein ASXL1

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