Mutant DNA methylation regulators endow hematopoietic stem cells with the preleukemic stem cell property, a requisite of leukemia initiation and relapse

doi:10.1007/s11684-015-0423-x

Front. Med.

2015, Vol. 9

Issue (4) : 412-420 https://doi.org/10.1007/s11684-015-0423-x

REVIEW

Mutant DNA methylation regulators endow hematopoietic stem cells with the preleukemic stem cell property, a requisite of leukemia initiation and relapse

Yuting Tan,Han Liu,Saijuan Chen(

)

State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

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Abstract

Genetic mutations are considered to drive the development of acute myeloid leukemia (AML). With the rapid progress in sequencing technologies, many newly reported genes that are recurrently mutated in AML have been found to govern the initiation and relapse of AML. These findings suggest the need to distinguish the driver mutations, especially the most primitive single mutation, from the subsequent passenger mutations. Recent research on DNA methyltransferase 3A (DNMT3A) mutations provides the first proof-of-principle investigation on the identification of preleukemic stem cells (pre-LSCs) in AML patients. Although DNMT3A mutations alone may only transform hematopoietic stem cells into pre-LSCs without causing the full-blown leukemia, the function of this driver mutation appear to persist from AML initiation up to relapse. Therefore, identifying and targeting preleukemic mutations, such as DNMT3A mutations, in AML is a promising strategy for treatment and reduction of relapse risk.

Keywords preleukemic stem cell acute myeloid leukemia relapse DNMT3A

Corresponding Author(s): Saijuan Chen

Just Accepted Date: 23 September 2015 Online First Date: 26 October 2015 Issue Date: 26 November 2015

Cite this article:

Yuting Tan,Han Liu,Saijuan Chen. Mutant DNA methylation regulators endow hematopoietic stem cells with the preleukemic stem cell property, a requisite of leukemia initiation and relapse[J]. Front. Med., 2015, 9(4): 412-420.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-015-0423-x
https://academic.hep.com.cn/fmd/EN/Y2015/V9/I4/412

Fig.1 Essential features shared or varying among the HSC, pre-LSC, and LSC.

Fig.2 Three possible scenarios for AML evolution and relapse. Chemotherapy can kill blast cells (dark blue lightning arrow) in all three scenarios. Usually, pre-LSCs and LSCs are dormant cells resistant to conventional chemotherapy (the first scenario). The LSCs derived from more mature progenitor cells (the second and third scenario) are potentially less quiescent and more sensitive to chemotherapy (light blue lightning arrow). The preleukemic cells derived from progenitors rather than HSCs (the third scenario) may be less dormant and susceptible to chemotherapy. Pre-LMP, pre-leukemic myeloid progenitors; CMP, common myeloid progenitor.

Fig.3 Crosstalks among DNA methyltransferases (DNMTs), TETs, and IDH1/2. SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; 2-OG, 2-oxoglutarate; 2-HG, 2-hydroxyglutarate.

Fig.4 A schematic model of AML evolution from pre-LSC. The order and mutations of different clones may differ from one case to another. The same cell type is marked by the dash line. CMP, common myeloid progenitor.

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