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Open Access 01-12-2016 | Research

DNMT3A mutation leads to leukemic extramedullary infiltration mediated by TWIST1

Authors: Jie Xu, Wu Zhang, Xiao-Jing Yan, Xue-Qiu Lin, Wei Li, Jian-Qing Mi, Jun-Min Li, Jiang Zhu, Zhu Chen, Sai-Juan Chen

Published in: Journal of Hematology & Oncology | Issue 1/2016

Abstract

Background

DNMT3A mutations are frequently discovered in acute myeloid leukemia (AML), associated with poor outcome. Recently, a relapse case report of AML extramedullary disease has showed that AML cells harboring DNMT3A variation were detected in the cerebral spinal fluid. However, whether a causal relationship exists between DNMT3A mutation (D3Amut) and extramedullary infiltration (EMI) is unclear.

Methods

We took advantage of DNMT3A (R882C) mutation-carrying AML cell strain, that is, OCI-AML3, assessing its migration ability in vitro and in vivo. By RNA interfering technology and a xenograft mouse model, we evaluated the effect of DNMT3A mutation on cell mobility and explored the possible mechanism.

Results

OCI-AML3 displayed extraordinary migration ability in vitro and infiltrated into meninges of NOD/SCID mice after intravenous transfusion. We found that this leukemic migration or infiltration capacity was significantly compromised by the knockdown of DNMT3A mutant. Notably, TWIST1, a critical inducer of epithelial–mesenchymal transition, which underlies the metastasis of carcinomas, was highly expressed in association with R882 mutations. Abrogation of TWIST1 in DNMT3A mutated cells considerably weakened their mobility or infiltration.

Conclusions

Our results demonstrate that D3Amut in OCI-AML3 strain enhances leukemic aggressiveness by promoting EMI process, which is partially through upregulating TWIST1.

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Title: DNMT3A mutation leads to leukemic extramedullary infiltration mediated by TWIST1
Authors: Jie Xu
Wu Zhang
Xiao-Jing Yan
Xue-Qiu Lin
Wei Li
Jian-Qing Mi
Jun-Min Li
Jiang Zhu
Zhu Chen
Sai-Juan Chen
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2016
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-016-0337-3

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Abstract

Background

Methods

Results

Conclusions

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