JunB Limits Hematopoietic Stem Cell (HSC) Functions as a Protective Mechanism against Initiation of Myeloid Malignancy

The JunB/AP-1 transcription factor plays a crucial role in controlling homeostasis of the hematopoietic stem cell (HSC) compartment and functions as a tumor suppressor in mice. We have previously demonstrated that mice lacking JunB accurately recapitulate important clinical aspects of human myeloid malignancies, including chronic myelogenous leukemia(CML). Using this model, we have shown that leukemia-initiating stem cells (LSCs) can arise from the hematopoietic stem cell (HSC) compartment. Now, we have identified the mechanisms by which JunB regulates HSC functions and discovered how inactivation of this key transcription factor leads to HSC transformation into LSCs that overproduce myeloid progenitors and drive myeloproliferative disease (MPD) development in vivo. We found that JunB normally controls the proliferation of the long-term HSCs (LT-HSCs) by regulating the expression levels of key cell cycle regulators, including the CKI p57 and the polycomb group gene Bmi1, and limits the rate at which LT-HSCs produce myeloid progenitors by maintaining appropriate responsiveness to both Notch and TGF-β signaling pathways. These functions place JunB at the center of a complex network of intrinsic and extrinsic regulations that ensure coordinate regulation of HSC proliferation and differentiation, independently of LT-HSC maintenance and self-renewal activity. These results provide a mechanism for disease initiation in a broad range of human myeloid malignancies, including those in which JunB inactivation has already been reported. Moreover, they expand our understanding of the normal biology of the HSC compartment and provide a mechanism to explain how mutations that increase the proliferation of a single LT-HSC can become dominant and lead to the expansion of an aberrant clone within the otherwise normal HSC compartment. Understanding clonal dominance of LT-HSCs is clearly at the root of designing new therapeutic treatments for a broad spectrum of hematological malignancies.