The m6A reader IGF2BP3 promotes acute myeloid leukemia progression by enhancing RCC2 stability

Abstract

N6-methyladenosine (m6A) is the most abundant posttranscriptional modification of mRNA in eukaryotes. Recent evidence suggests that dysregulated m6A-associated proteins and m6A modifications play a pivotal role in the initiation and progression of diseases such as cancer. Here, we identified that IGF2BP3 is specifically overexpressed in acute myeloid leukemia (AML), a subtype of leukemia associated with poor prognosis and high genetic risk. IGF2BP3 is required for maintaining AML cell survival in an m6A-dependent manner, and knockdown of IGF2BP3 dramatically suppresses the apoptosis, reduces the proliferation, and impairs the leukemic capacity of AML cells in vitro and in vivo. Mechanistically, IGF2BP3 interacts with RCC2 mRNA and stabilizes the expression of m6A-modified RNA. Thus, we provided compelling evidence demonstrating that the m6A reader IGF2BP3 contributes to tumorigenesis and poor prognosis in AML and can serve as a target for the development of cancer therapeutics.

Leukemia: Key component of disease progression identified

Inhibiting a protein that is overexpressed in the bone marrow of acute myeloid leukemia patients may prove valuable in treating the disease. Recent research has demonstrated the important role played by epigenetics in cancers – for example, disruption to a common mRNA modification known as m6A can result in cancer initiation and progression. Jianchuan Deng and co-workers at Chongqing Medical Universit0y, China, examined the role of an m6A-related protein called IGF2BP3 in mice models and samples from leukemia patients. IGF2BP3 was overexpressed in patients’ bone marrows, the levels of the protein correlating with extent of proliferation of leukemia cells and poor prognosis. IGF2BP3 stabilises the activity of a known cancer-related protein, promoting leukemia progression. Blocking IGF2BP3 expression reduced cell proliferation and impaired activity of leukemic cells, suggesting the protein may be a useful therapeutic target.