Researchers Identify Stem Cell Origin of AML

For most patients with acute myeloid leukemia (AML), the disease seems to arise suddenly, with no previous indication, raising questions about its origin and evolution. Researchers have now identified ancestral pre-leukemic hematopoietic stem cells (HSC) that may give rise to the disease.

These ancestral stem cells are present at diagnosis, can survive chemotherapy, and persist in the bone marrow, potentially leading to disease recurrence, according to a report published in February (Nature 2014;506:328–33). These observations may lead to the identification of pre-leukemic HSCs in healthy individuals, and the HSCs may be viable targets for intervention.

John E. Dick, PhD, a researcher at the Princess Margaret Cancer Centre in Toronto and the University of Toronto in Canada, and his colleagues sequenced 103 commonly mutated leukemia genes in 83 patients. In roughly 25% of the samples, they identified mutations in the DNMT3A gene in the AML cells. The researchers found another well-known leukemia mutation in NPM1c, which occurred in 88% of the samples that carried mutations in DNMT3A.

However, the analysis turned up an unexpected surprise: T cells in 15 patients also contained the DNMT3A mutations, but not the NPM1c mutation. The presence of the DNMT3A mutations in both T cells, which are of the lymphoid lineage, and AML cells, of the myeloid lineage, coupled with the lack of the NPM1c mutation in T cells, led the researchers to theorize that the DNMT3A mutations were cancer drivers in ancestral HSCs that give rise to both lineages.

Further studies confirmed that suggestion, as they identified HSCs with DNMT3A mutations but without NPM1c mutations. DNMT3A mutations were also identified in HSCs in blood from patients who had already undergone chemotherapy—including patients in remission and those whose disease had recurred.

Researchers are already investigating DNMT3A as a target for therapy, but a drug can't come fast enough for patients who've already been diagnosed.

“The patients we need to follow are those in remission, because the recurrence rate is very high,” Dick says. “In patients with these pre-leukemic cells, we want to know, what's the risk the disease will recur? We're working hard to answer that question.”

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