Editors' ChoiceCancer

To Catch a Pre-Leukemia

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Science Translational Medicine  05 Mar 2014:
Vol. 6, Issue 226, pp. 226ec40
DOI: 10.1126/scitranslmed.3008713

Cancer has been a curable disease for a long time… if we catch it early. An estimated 80% of cancers can be cured if detected early enough. In contrast, late-stage cancers become so adept at circumventing the body’s many defensive mechanisms that they nearly always eventually acquire resistance to therapies. This argument has led many leading oncologists to contend that the most important breakthroughs in reducing cancer mortality will derive from improved early-detection strategies. More generally, therapies that fail to eradicate cells harboring mutations that arise early in oncogenesis may leave intact the generative wellspring of future tumors. Thus, improved cancer detection and treatment may critically depend on our ability to define genomic events that occur early in cancer progression. Now, Shlush et al. report the identification of mutations that arise in pre-leukemic hematopoietic stem cells and define early-stage events in the progression to acute myeloid leukemia (AML).

While studying targeting sequencing data from AML patients, the authors unexpectedly observed that three of four patients with DNMT3A mutations also harbored DNMT3A mutations in normal T cells at low allele frequency (1 to 20%). Other commonly mutated genes, such as NPM1c, were not mutated in T cells. These observations held up in a larger cohort; 12 of 17 AML samples harboring DNMT3A mutations also harbored DNMT3A, but not NPM1c, mutations in normal T cells. Using cell-sorting strategies to isolate hematopoietic stem and progenitor cells at various states of differentiation, the authors observed that DNMT3A mutations largely arose in hematopoietic stem cells (HSCs) and preceded NPM1c mutations during leukemogenesis. Comparison of diagnostic, remission, and relapse patients suggested that DNMT3Amut HSCs survived chemotherapy and expanded during remission. Mouse xenograft experiments indicated that cells from relapse samples generated leukemic grafts, whereas peripheral blood cells from diagnostic DNMT3Amut AML samples generated multilineage grafts with increased DNMT3Amut allele frequency as compared with that of cells at early time points after transplantation. These observations support the notion that DNMT3Amut HSCs are pre-leukemic cells, with competitive growth advantage over DNMT3Awt HSCs.

Deconvoluting the functional mutations that occur at early stages of leukemogenesis has implications for both therapy and early detection. In DNMT3Amut AML patients, therapies designed to eliminate DNMT3Amut HSCs, rather than just reduce the overall number of tumor cells, may be more likely to achieve durable response by cutting off the reservoir of pre-leukemic progenitors. Moreover, DNMT3A mutations in healthy individuals may serve as a risk marker of progression to AML. Thus, screening for DNMT3A mutations may be used to suggest preventive therapeutic measures or increased monitoring of additional mutations, such as NPM1c, that may occur during leukemogenesis.

L. I. Shlush et al., Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 506, 328–333 (2014). [Abstraact]

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