Without JunB, HSCs lose their ability to respond to signals from the protein receptors Notch and TGF-beta, which reside on the cells' surface and play critical roles in determining cell fate.
"By uncovering this mechanism, we might one day be able to determine the difference between normal HSCs and leukemic stem cells in gene regulatory networks. This could allow us to develop more targeted therapies. These kinds of therapeutic applications are still down the road, but they can happen very quickly in the blood/leukemia field," says Passegué.
Passegué's study represents a turnabout from other research, which has demonstrated that mutated HSC that cause leukemia burn out at a faster rate than normal HSCs. In contrast, this study shows that JunB does not effect the cells' potential for unlimited self-renewal.
The researchers demonstrated this by treating both JunB-deficient mice and control mice with the powerful chemotherapy drug 5-FU, which was given to deplete regenerating HSCs. As expected, JunB-deficient mice consistently displayed higher levels of myeloid lineage than the control group, indicating constant regeneration of a myeloproliferative disease from JunB-deficient HSCs that persisted after treatment. When researchers compared survival rates of the animals during several cycles of treatment, they found little difference between the two groups, indicating that JunB-deficient HSCs do not exhaust faster than the control HSCs.
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