Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.
Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.
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DOI：
10.1038/nature13038
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发表时间：
2014-02-20
期刊：
影响因子：
64.8
通讯作者：
Dick JE
中科院分区：
文献类型：
--
作者：
Shlush LI;Zandi S;Mitchell A;Chen WC;Brandwein JM;Gupta V;Kennedy JA;Schimmer AD;Schuh AC;Yee KW;McLeod JL;Doedens M;Medeiros JJ;Marke R;Kim HJ;Lee K;McPherson JD;Hudson TJ;HALT Pan-Leukemia Gene Panel Consortium;Brown AM;Yousif F;Trinh QM;Stein LD;Minden MD;Wang JC;Dick JE
In acute myeloid leukemia (AML), the cell of origin, nature and biological consequences of initiating lesions and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukemic phase. Here, highly purified hematopoietic stem cells (HSC), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent DNMT3a mutations (DNMT3amut) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3amut-bearing HSC exhibited multilineage repopulation advantage over non-mutated HSC in xenografts, establishing their identity as pre-leukemic-HSC (preL-HSC). preL-HSC were found in remission samples indicating that they survive chemotherapy. Thus DNMT3amut arises early in AML evolution, likely in HSC, leading to a clonally expanded pool of preL-HSC from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance.
