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Among patients with AML, the detection of molecular minimal residual disease during complete remission had significant independent prognostic value with respect to relapse and survival rates, but the detection of persistent mutations that are associated with clonal hematopoiesis did not have such prognostic value within a 4-year time frame. (Funded by the Queen Wilhelmina Fund Foundation of the Dutch Cancer Society and others.).

Aberrant DNA hypermethylation contributes to myeloid leukemogenesis by silencing structurally normal genes involved in hematopoiesis. MicroRNAs (miRNAs) are noncoding RNAs that regulate gene expression by targeting protein-coding mRNAs. Recently, miRNAs have been shown to play a role as both targets and effectors in gene hypermethylation and silencing in malignant cells. In the current study, we showed that enforced expression of miR-29b in acute myeloid leukemia cells resulted in marked reduction of the expression of DNA methyltransferases DNMT1, DNMT3A, and DNMT3B at both RNA and protein levels. This in turn led to decrease in global DNA methylation and reexpression of p15 INK4b and ESR1 via promoter DNA hypomethylation. Although down-regulation of DNMT3A and DNMT3B was the result of a direct interaction of miR-29b with the 3 untranslated regions of these genes, no predicted miR-29b interaction sites were found in the DNMT1 IntroductionDNA methylation consists of an enzymatic addition of a methyl group at the carbon 5 position of cytosine in the context of the sequence 5Ј-cytosine-guanosine (CpG) and is mediated by DNA methyltransferases (DNMTs). 1 The promoter regions of approximately 50% of human genes contain regions of DNA with a cytosine and guanine content greater than expected (so-called CpG islands) that, once hypermethylated, mediate gene transcriptional silencing. 2 Distinct roles in genomic methylation have been reported for DNMT isoforms. Whereas DNMT1 preferentially replicates already existing methylation patterns, DNMT3A and 3B are responsible for establishing de novo methylation. 2 Silencing of structurally normal tumor suppressor genes by aberrant DNA hypermethylation has been reported in hematologic malignancies, including subsets of acute myeloid leukemia (AML). 3,4 Although the mechanisms leading to aberrant DNA hypermethylation remain to be fully elucidated, increased levels of DNMT1 and DNMT3A and 3B have been observed in malignant myeloid blasts compared with normal bone marrow (BM) mononuclear cells (MNCs), suggesting that DNMT overexpression contributes to gene promoter hypermethylation and in turn to leukemogenesis. 4 Growing evidence supports a role for microRNAs (miRNAs) as both targets and effectors in aberrant mechanisms of DNA hypermethylation. 5,6 miRNAs are noncoding RNAs of 19 to 25 nucleotides in length that regulate gene expression by inducing translational inhibition or cleavage of their target mRNAs through base pairing at partially or fully complementary sites. 7 Several groups have shown that miRNAs are altered in human malignancies and can function as tumor suppressor genes or oncogenes through expression regulation of their target genes. 7 Similar to tumor suppressor genes, miRNAs with tumor suppressor activity are often located in deleted genomic areas or are silenced by mutations or promoter hypermethylation in malignant cells. 5,[8][9][10] Saito et al recently demonstrated that miR-127 is silenced by promoter DNA hypermethylation and down-regulated in human bladder ...

Approximately 30% to 50% of adults with acute lymphoblastic leukemia (ALL) in hematologic complete remission after multiagent therapy exhibit minimal residual disease (MRD) by reverse transcriptase-polymerase chain reaction or flow cytometry. MRD is the strongest predictor of relapse in ALL. In this open-label, single-arm study, adults with B-cell precursor ALL in hematologic complete remission with MRD (≥10) received blinatumomab 15 µg/m per day by continuous IV infusion for up to 4 cycles. Patients could undergo allogeneic hematopoietic stem-cell transplantation any time after cycle 1. The primary end point was complete MRD response status after 1 cycle of blinatumomab. One hundred sixteen patients received blinatumomab. Eighty-eight (78%) of 113 evaluable patients achieved a complete MRD response. In the subgroup of 110 patients with Ph-negative ALL in hematologic remission, the Kaplan-Meier estimate of relapse-free survival (RFS) at 18 months was 54%. Median overall survival (OS) was 36.5 months. In landmark analyses, complete MRD responders had longer RFS (23.6 vs 5.7 months; = .002) and OS (38.9 vs 12.5 months; = .002) compared with MRD nonresponders. Adverse events were consistent with previous studies of blinatumomab. Twelve (10%) and 3 patients (3%) had grade 3 or 4 neurologic events, respectively. Four patients (3%) had cytokine release syndrome grade 1, n = 2; grade 3, n = 2), all during cycle 1. After treatment with blinatumomab in a population of patients with MRD-positive B-cell precursor ALL, a majority achieved a complete MRD response, which was associated with significantly longer RFS and OS compared with MRD nonresponders. This study is registered at www.clinicaltrials.gov as #NCT01207388.