Evolution of Cytogenetically Normal Acute Myeloid Leukemia During Therapy and Relapse: An Exome Sequencing Study of 50 Patients

Abstract

Purpose: To study mechanisms of therapy resistance and disease progression, we analyzed the evolution of cytogenetically normal acute myeloid leukemia (CN-AML) based on somatic alterations. Experimental Design: We performed exome sequencing of matched diagnosis, remission, and relapse samples from 50 CN-AML patients treated with intensive chemotherapy. Mutation patterns were correlated with clinical parameters. Results: Evolutionary patterns correlated with clinical outcome. Gain of mutations was associated with late relapse. Alterations of epigenetic regulators were frequently gained at relapse with recurring alterations of KDM6A constituting a mechanism of cytarabine resistance. Low KDM6A expression correlated with adverse clinical outcome, particularly in male patients. At complete remission, persistent mutations representing preleukemic lesions were observed in 48% of patients. The persistence of DNMT3A mutations correlated with shorter time to relapse. Conclusions: Chemotherapy resistance might be acquired through gain of mutations. Insights into the evolution during therapy and disease progression lay the foundation for tailored approaches to treat or prevent relapse of CN-AML. Clin Cancer Res; 24(7); 1716–26. ©2018 AACR.

Clonal evolution of acute myeloid leukemia from diagnosis to relapse

“…Recently, it was reported that in AML cells after allogeneic stem cell transplantation (SCT), no relapse‐specific mutational patterns were observed . In contrast, other studies found an enrichment of WT1 mutations in AML relapse after chemotherapy as well as after SCT . Although the gain of WT1 mutations were not significant in any of the studies, combined analysis of two independent cohorts showed a significant association of WT1 mutations with relapse after SCT suggesting a common evolutionary pattern (Figure ).…”

“…Five diagnosis/remission/relapse triplets were analyzed by WES and eight diagnosis/relapse pairs were analyzed by GPS . Relapse of the largest cytogenetic subgroup of AML, patients with normal karyotype, was characterized by 50 matched diagnosis/remission/relapse triplets using WES, followed by GPS for variant validation . Very recently, Cocciardi et al described the mutational spectrum at diagnosis and relapse of NPM1 mutated AML in 129 cases using GPS of five commonly mutated genes ( DNMT3A , FLT3 , NRAS , IDH1 , and IDH2 ).…”

“…Interestingly in NPM1 + / NPM1 − AML patients, FLT3 ‐ITDs were not detected at relapse although present in 18/61 NPM1 + diagnostic samples, pointing towards the development of an independent AML at relapse . FLT3 point mutations are often lost in the CN‐AML cohort and NPM1 + patients, while gained in patients of the FLT3 ‐ITD AML cohort . DNMT3A is stably mutated in most of the patients without any loss in the CN‐AML cohort, still recurrently lost in 2/18 FLT3 ‐ITD patients and 6/91 NPM1 + patients .…”

“…DNMT3A is stably mutated in most of the patients without any loss in the CN‐AML cohort, still recurrently lost in 2/18 FLT3 ‐ITD patients and 6/91 NPM1 + patients . Additional examples for stable mutations detected in multiple cohorts include IDH1 and IDH2 , although these mutations are also gained in several patients . Genes specifically mutated at diagnosis include NRAS , KIT , and PTPN11 .…”

MBD3/NuRD loss participates with KDM6A program to promoteDOCK5/8expression and Rac GTPase activation in human acute myeloid leukemia

“…Attenuation of H3K27 demethylase activity of KDM6A has also been shown to enhance tumor cell radiosensitivity (25). It is important to mention that, unlike in primary AML, low KDM6A expression has been observed in relapsed AML patients (28), which further suggests that the overall contribution of KDM6A in tumorigenesis is spatiotemporally regulated.…”