Abstract
We previously reported that microRNA (miR)-29b is down-regulated and has a tumor suppressor role in acute myeloid leukemia (AML). However, little is known about the mechanisms responsible for miR-29b expression downregulation in AML. In this work we screened for mutations that could affect miR-29b expression. Using Sanger sequencing, we identified a germline thymidine (T) base deletion within the miR-29b-1/miR-29a cluster precursor in 16% of AML patients. Remarkably we found a significant enrichment for the presence of the miR-29 polymorphism in core binding factor (CBF) newly diagnosed AML patients (n = 61/303; 20%) with respect to age, sex and race matched controls (n = 43/402:11%, P < 0.01). Mechanistically, this polymorphism affects the expression ratio of mature miR-29b and miR-29a by dampening the processing of miR-29a. RNA immunoprecipitation assays showed reduced DROSHA binding capacity to the polymorphism with respect to the controls. Finally, we showed that this polymorphism negatively impacts the ability of miR-29b-1/miR-29a cluster to target MCL-1 and CDK6, both known miR-29 targets.
Highlights
Acute myeloid leukemia (AML) is a highly heterogeneous malignant disease of the hematopoietic system characterized by a clonal accumulation of immature myeloid precursor cells in the bone marrow (BM) and peripheral blood (PB) [1]
We found an enrichment for the presence of the miR-29 polymorphism in acute myeloid leukemia (AML) cases with core binding factor (CBF) leukemia (n = 3/12: 25%) compared to controls (n = 43/402:11%) (Supplementary Table 1 and Figure 1C)
To further explore this finding we screened for the presence of this polymorphism in a larger second cohort of 303 samples of newly diagnosed AML patients with t(8;21) (n = 131) and inv(16) (n = 172) obtained from the Cancer and leukemia group B (CALGB)/ Alliance leukemia www.impactjournals.com/oncotarget tissue bank (See Tables 2 and 3 for patients characteristics)
Summary
Acute myeloid leukemia (AML) is a highly heterogeneous malignant disease of the hematopoietic system characterized by a clonal accumulation of immature myeloid precursor cells in the bone marrow (BM) and peripheral blood (PB) [1]. Structural genetic alterations, including gene deletion, inversions and translocations have been found in about 55 to 60% of AML patients [1, 2] These alterations, for the most part, represent the initial and contributing events leading to malignant transformation [1, 2]. We have shown that miR-29b is central to regulation of both DNA methylation and tyrosine kinase receptor activities in leukemia cells [20, 22]. These studies support a tumor suppressor function for miR-29b in AML
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