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IFN regulatory factor-8 (IRF-8, previously known as ICSBP) is a key transcription factor driving the differentiation of granulocyte\monocyte progenitor (GMP) cells toward monocyte\macrophage lineage. The promyelocytic leukemia (PML) gene is an immediate target gene regulated by IRF-8 in response to IFN-γ activation. PML is a multifunctional protein that has many isoforms serving as the scaffold components for nuclear bodies (NBs) engaged in numerous proteins interactions. The role of PML in the retinoic acid pathway that drives GMPs to granulopoiesis is documented in the literature. Here, we show that PML is also involved in monopoiesis by mediating some of the IRF-8 activities during the differentiation of murine-derived bone marrow macrophages (BMMs). PML silencing resulted in altered expression level of key transcription factors essential for monopoiesis that was accompanied by silencing of typical myeloid-specific genes. Interestingly, this altered expression resembled that of the GMPs and that of BMMs derived from IRF-8(-/-) mice altogether supporting the role of PML in monopoiesis. Further, PML silencing led to reduced colony-forming capacity of bone marrow cells highlighting the dual function of PML in myelopoiesis. Last, PML overexpression only partially rescued the phenotype of IRF-8(-/-) BMMs. Together, our data show that PML is an important factor for monopoiesis and not solely for granulopoiesis. This suggests that PML-NBs respond to an incoming signal that affects the fate of GMP driving cell differentiation to granulocytes or monocytes.

PML is a key component for the differentiation of myeloid progenitor cells to macrophages