Leukemic Stem Cell Gene Expression Signature and Clinical Outcomes in Acute Myeloid Leukemia—Reply

In Reply: The important recent characterization of mutations in the DNA methyltransferase gene DNMT3A and association with adverse patient outcomes¹ was performed on 1 of the patient cohorts included in our study. This permitted us to examine the relationship between LSC scores and DNMT3A mutation status. Of 184 patients with available gene expression profiles, 41 represented acute promyelocytic leukemia, a distinct AML entity in which the LSC signature expression is significantly lower and DNMT3A mutations are rare.²DNMT3A was sequenced in 136 of the remaining 143 samples, with 35 harboring mutations and 101 being wild-type (9 cases had no data for DNMT3A). There was no significant difference in LSC score between patients stratified by the presence or absence of DNMT3A mutations, either across all AML subtypes (n = 135; P = .93 by t test) or across only normal-karyotype AML (n = 71; P = .40). This is perhaps not surprising given the heterogeneity of AML. Gene expression profiles reflect complex interactions between mutations, karyotypic abnormalities, and other processes. From this viewpoint, the LSC score represents an integration of multiple factors converging on activation of a stem-cell–like phenotype and transcriptional program. Dissection of the causal processes involved will require further detailed functional studies.