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McMaster University
Research published in Cancer Cell suggests a molecular signature can be used to predict which patients with myelodysplastic syndromes (MDS) will develop acute myeloid leukemia (AML).
Investigators found that progressive removal of glycogen synthase kinase-3 (GSK-3) signaling via GSK-3β deletion in hematopoietic stem cells (HSCs) results in an MDS-like state.
And when both GSK-3β and GSK-3α are deleted, AML develops.
“We’ve found that the transition from healthy to cancerous blood stem cells happens in clear, compartmentalized steps,” said study author Mick Bhatia, PhD, of McMaster University in Hamilton, Ontario, Canada. “We’ve identified 2 steps in that staircase.”
Specifically, the investigators found that deleting GSK-3β in HSCs led to the generation of self-renewing cells dubbed MDS-initiating cells. These cells proved capable of sustaining MDS in vivo.
Next, the team found that GSK-3β deletion drives Wnt/Akt/mTOR signaling and can induce AML in the absence of GSK-3α.
They noted that GSK-3α has no biological impact on hematopoiesis, but GSK-3α deletion is necessary for the evolution of MDS to AML that occurs in the absence of GSK-3β.
The investigators then defined a molecular signature of GSK-3β-deficient HSCs that could predict transformation to AML in patients with MDS.
The team tested the utility of this 63-gene signature using blood samples that were previously collected from patients with MDS, some of whom ultimately developed AML. The results showed the signature could accurately predict which patients would develop AML and which would not.
“[O]ur next step is to go beyond better predictive measures for the development of a blood cancer and use this predictive gene expression as a target for drugs to prevent AML from developing altogether,” Dr Bhatia said. “This will be part of a new era of genetic-based drug discovery.”
