Cytokine-Regulated GADD45G Induces Differentiation and Lineage Selection in Hematopoietic Stem Cells

Summary

The balance of self-renewal and differentiation in long-term repopulating hematopoietic stem cells (LT-HSC) must be strictly controlled to maintain blood homeostasis and to prevent leukemogenesis. Hematopoietic cytokines can induce differentiation in LT-HSCs; however, the molecular mechanism orchestrating this delicate balance requires further elucidation. We identified the tumor suppressor GADD45G as an instructor of LT-HSC differentiation under the control of differentiation-promoting cytokine receptor signaling. GADD45G immediately induces and accelerates differentiation in LT-HSCs and overrides the self-renewal program by specifically activating MAP3K4-mediated MAPK p38. Conversely, the absence of GADD45G enhances the self-renewal potential of LT-HSCs. Videomicroscopy-based tracking of single LT-HSCs revealed that, once GADD45G is expressed, the development of LT-HSCs into lineage-committed progeny occurred within 36 hr and uncovered a selective lineage choice with a severe reduction in megakaryocytic-erythroid cells. Here, we report an unrecognized role of GADD45G as a central molecular linker of extrinsic cytokine differentiation and lineage choice control in hematopoiesis.

Graphical Abstract

Highlights

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  Molecular mechanism of cytokine-mediated differentiation induction in LT-HSCs

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  Cytokine-regulated GADD45G induces and accelerates differentiation in LT-HSCs

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  The absence of GADD45G increases the self-renewal capacity in LT-HSCs

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  GADD45G-induced program selects for myelomonocytic and lymphoid lineages

Abstract

Rieger and colleagues report an unrecognized function of the tumor suppressor GADD45G as a molecular link of differentiation-promoting cytokine signaling and rapid differentiation induction in hematopoiesis. Cytokine-regulated GADD45G induces and accelerates hematopoietic stem cell differentiation and overrides the self-renewal program by specifically activating MAP3K4-mediated MAPK p38. Videomicroscopy-based single stem cell tracking further revealed a GADD45G-mediated selective lineage choice against megakaryocytic-erythroid fate.