AML Cells Block HSC Differentiation

When acute myeloid leukemia (AML) causes bone marrow failure, the common explanation is that the proliferation of AML cells crowds out normal hematopoietic stem cells (HSC). However, results of a study by British researchers in the Proceedings of the National Academy of Sciences suggest that AML cells inhibit the differentiation of HSCs rather than displacing them.

If their findings are correct, bone marrow failure caused by the disease might be treated by agents that release HSCs from AML-induced inhibition, allowing them to challenge the AML cells for supremacy in the bone marrow.

“Maybe the HSCs can win the battle, reclaim the bone marrow, and kill off the AML cells,” says David Taussig, FRCPath, MRCP, PhD, senior lecturer and consultant in hematology at Barts Cancer Institute at Queen Mary University of London, UK, and senior author of the study.

Taussig and his colleagues injected 111 immunodeficient mice with human AML cells. They then sacrificed the mice at regular intervals, collected bone marrow, and used antibodies to quantify the AML cells, mouse HSCs, progenitor cells, and blood cells produced by the HSCs.

When the number of AML cells accounted for 22% to 84% of the bone marrow cells, the numbers of HSCs and progenitor cells diverged: the number of HSCs held steady—or even increased in some instances—while the number of progenitor cells declined significantly. The researchers say this is evidence that HSCs survive the invasion of AML cells but that their normal differentiation is suspended.

When the normal HSCs were removed from the leukemic environment, the researchers found that they differentiated as usual, suggesting that HSC inhibition by AML cells can be reversed.

To exclude the possibility that mere transplantation of cells might affect HSCs, the researchers injected mice with AML cells that proliferate poorly. After 14 weeks, the high-HSC, low-progenitor pattern seen with proliferative AML cells did not emerge.

Following up their findings in humans, Taussig's team compared the bone marrow of 16 people newly diagnosed with AML with that of healthy control subjects. The AML patients had just 3.5 progenitor cells per HSC compared with 41 per HSC in the controls.

The next step, says Taussig, is to shed some light on how AML cells influence HSCs. TGFβ, a cytokine with antiproliferative effects, might play a role, he says.

Ultimately, researchers want to identify agents that could rouse HSCs into action. Noting a recent positive result published in the New England Journal of Medicine for a thrombopoietin mimetic as a treatment for severe aplastic anemia, Taussig says thrombopoietin agonists might be effective.

“The leukemia is putting the hematopoietic stem cells to sleep,” says Taussig, “but we may be able to wake them up again.”