A new study has shown that hematopoietic stem cells (HSCs) can acquire mutations in DNMT3A, and this may be the first step in initiating acute myeloid leukemia (AML).
These HSCs also appear to be a means of treatment resistance and may trigger relapse in patients with AML, investigators reported in Nature.
“Our discovery lays the groundwork to detect and target the pre-leukemic stem cell and thereby potentially stop the disease at a very early stage, when it may be more amenable to treatment,” said study author John Dick, PhD, of the University of Toronto in Ontario, Canada.
“Now, we have a potential tool for earlier diagnosis that may allow early intervention before the development of full AML. We can also monitor remission and initiate therapy to target the pre-leukemic stem cell to prevent relapse.”
Dr Dick and his colleagues analyzed 71 samples from AML patients and discovered that 17 of them (24%) carried mutations in DNMT3A. Fifteen of those samples (88%) also had mutated NPM1.
Both mutations were present in patients’ blasts. But 12 patients (70.5%) had T cells that contained DNMT3A mutations but no NPM1 mutations. FLT3-ITD mutations were also present in blasts but not T cells in 2 patients.
These results suggest DNMT3A mutations arise earlier than NPM1 and FLT3-ITD mutations, the researchers said.
To determine the origin of mutated DNMT3A, they analyzed hematopoietic stem and progenitor cell populations from 11 patients with DNMT3A and NPM1 mutations.
While both types of mutations were present in CD33+ blasts, mutant DNMT3A was present without mutant NPM1 across the spectrum of mature and progenitor cell populations.
Experiments in mice revealed that DNMT3A-mutant HSCs had a multilineage repopulation advantage over non-mutant HSCs. This, the investigators said, establishes the mutant cells as pre-leukemic HSCs.
The team also found the pre-leukemic HSCs in samples taken from AML patients in remission, which showed that the cells survived chemotherapy.
The researchers therefore concluded that DNMT3A mutations arise early in AML evolution and lead to a clonally expanded pool of pre-leukemic HSCs from which AML develops.
“By peering into the ‘black box’ of how cancer develops during the months and years prior to when it is first diagnosed, we have demonstrated a unique finding,” Dr Dick said. “People tend to think relapse after remission means chemotherapy didn’t kill all the cancer cells.”
“Our study suggests that, in some cases, the chemotherapy does, in fact, eradicate AML. What it does not touch are the pre-leukemic stem cells that can trigger another round of AML development and, ultimately, disease relapse.”
Dr Dick believes this finding could spawn accelerated drug development to specifically target DNMT3A. The discovery should also provide impetus for researchers to look for pre-cancerous cells in AML patients with other mutations.
