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 ...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.展开更多
Acute myeloid leukemia(AML)has been shown to undergo multiple acquired mutations in hematopoietic cell lineages over years before becoming clinically apparent.The early stage of AML(before it becomes clinically recogn...Acute myeloid leukemia(AML)has been shown to undergo multiple acquired mutations in hematopoietic cell lineages over years before becoming clinically apparent.The early stage of AML(before it becomes clinically recognizable)may be characterized by acquisition of some,but not all,leukemia-related somatic mutations in hematopoietic stem cells(HSCs).The physiological roles of these mutations remain puzzling.These HSCs have been termed as preleukemic HSCs.However,those frequent acquired somatic mutations are also found in healthy aging adults,namely,“age-related clonal hematopoiesis.”Multiple studies have demonstrated that the preleukemic HSCs survive through chemotherapy and then contribute to the relapse and the development of de novo AML.Whether preleukemic HSCs should be targeted or whether a preventive therapy should be considered for those individuals remains to be determined.This article aims to shed light on this special subject and to discuss the roles of preleukemic HSCs in leukemogenesis.展开更多
文摘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.
基金This work was supported by grants from the Ministry of Science and Technology of China(2016YFA0100600,2017YFA0103400)the National Natural Science Foundation of China(81861148029,81730006,81922002,81870086)CAMS Initiative for Innovative Medicine(2019-I2M-1-006,2017-I2M-3-009).
文摘Acute myeloid leukemia(AML)has been shown to undergo multiple acquired mutations in hematopoietic cell lineages over years before becoming clinically apparent.The early stage of AML(before it becomes clinically recognizable)may be characterized by acquisition of some,but not all,leukemia-related somatic mutations in hematopoietic stem cells(HSCs).The physiological roles of these mutations remain puzzling.These HSCs have been termed as preleukemic HSCs.However,those frequent acquired somatic mutations are also found in healthy aging adults,namely,“age-related clonal hematopoiesis.”Multiple studies have demonstrated that the preleukemic HSCs survive through chemotherapy and then contribute to the relapse and the development of de novo AML.Whether preleukemic HSCs should be targeted or whether a preventive therapy should be considered for those individuals remains to be determined.This article aims to shed light on this special subject and to discuss the roles of preleukemic HSCs in leukemogenesis.
