miR-9 is a tumor suppressor in pediatric AML with t(8;21)

Abstract

MicroRNAs (miRNAs) play a pivotal role in the regulation of hematopoiesis and development of leukemia. Great interest emerged in modulating miRNA expression for therapeutic purposes. In order to identify miRNAs, which specifically suppress leukemic growth of acute myeloid leukemia (AML) with t(8;21), inv(16) or mixed lineage leukemia (MLL) rearrangement by inducing differentiation, we conducted a miRNA expression profiling in a cohort of 90 cytogenetically characterized, de novo pediatric AML cases. Four miRNAs, specifically downregulated in MLL-rearranged, t(8;21) or inv(16) AMLs, were characterized by their tumor-suppressive properties in cell lines representing those respective cytogenetic groups. Among those, forced expression of miR-9 reduced leukemic growth and induced monocytic differentiation of t(8;21) AML cell lines in vitro and in vivo. The tumor-suppressive functions of miR-9 were specifically restricted to AML cell lines and primary leukemic blasts with t(8;21). On the other hand, these functions were not evident in AML blasts from patients with MLL rearrangements. We showed that miR-9 exerts its effects through the cooperation with let-7 to repress the oncogenic LIN28B/HMGA2 axis. Thus, miR-9 is a tumor suppressor-miR which acts in a stringent cell context-dependent manner.

Expression of micro RNA-9 in Patients with Acute Myeloid Leukemia and its Impact on Treatment Strategy

“…The results are in accordance with study performed by Emmrich et al (20) that showed down regulation of miR-9 in t(8;21) AML and explained that this low expression has oncogenic effect through its impact on specific genes (HMGA2, LIN28B) causing increased proliferation and decreased monocytic differentiation.…”

Developmental regulation of myeloerythroid progenitor function by the LIN28B-LET-7-HMGA2 axis

“…This observation agrees with previous studies that let-7 expression increases during terminal granulocyte differentiation (Wong et al, 2014) and that disruption of Lin28 expression can affect granulopoiesis (Wang et al, 2015). These results also parallel studies from the leukemia literature wherein let-7 activity has been shown to promote myeloblast differentiation Emmrich et al, 2013;Pelosi et al, 2013). Consistent with both transcriptional and posttranscriptional mechanisms of let-7 regulation, Lin28b deficiency alone did not fully recapitulate an adult-like myeloerythroid phenotype in the FL.…”

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16INK4a

“…For example, miR‐9 is highly expressed in primary breast cancers, where it promotes angiogenesis and metastasis (Ma et al ., 2010). In contrast, downregulation of miR‐9 has been reported in other cancer types, such as leukaemias (Emmrich et al ., 2014), suggesting cell‐ and tumour‐specific effects that might be explained by different expression levels of its targets.…”