Regulation of Hematopoiesis and Hematological Disease by TGF-β Family Signaling Molecules

Abstract

Throughout the lifetime of an individual, hematopoietic stem cells (HSCs) maintain the homeostasis of normal hematopoiesis through the precise generation of mature blood cells. Numerous genetic studies in mice have shown that stem-cell quiescence is critical for sustaining primitive long-term HSCs in vivo. In this review, we first examine the crucial roles of transforming growth factor β (TGF-β) and related signaling molecules in not only regulating the well-known cytostatic effects of these molecules but also governing the self-renewal capacity of HSCs in their in vivo microenvironmental niche. Second, we discuss the current evidence indicating that TGF-β signaling has a dual function in disorders of the hematopoietic system. In particular, we examine the paradox that, although intrinsic TGF-β signaling is essential for regulating the survival and resistance to therapy of chronic myelogenous leukemia (CML) stem cells, genetic changes that abrogate TGF-β signaling can lead to the development of several hematological malignancies.

Figure 1.

Transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signal transduction. Binding of TGF-β to dimeric TβRII enables ligand binding to dimeric TβRI and stimulates the kinase activity of TβRI. In Smad-mediated TGF-β signal transduction, TβRI phosphorylates cytoplasmic Smad2 and Smad3, which, following dissociation from TβRI, interact with Smad4. The trimeric complex of two receptor-activated Smad2 and/or Smad3 with one Smad4 then enters the nucleus, where it interacts with DNA-binding transcription factors (TFs) and coregulators at regulatory sequences of target genes, in a gene- and cell-context-dependent manner. BMP signaling operates in parallel and similarly to TGF-β signaling. In response to the binding of BMP ligands to the heteromeric receptor complex of BMPRII and BMPRI transmembrane kinases, receptor-activated Smad1 and Smad5 associate with Smad4 and translocate into the nucleus to activate or repress BMP target gene transcription.

Figure 2.

Hematopoietic hierarchy and transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signaling. Hematopoietic stem cells (HSCs) can self-renew and give rise to all mature hematopoietic cell lineages. Total HSCs can be classified into myeloid-biased (My)-HSCs, lymphoid-biased (Ly)-HSCs, and myeloid- and lymphoid-balanced (Bala)-HSCs. My-HSCs predominantly generate common myeloid progenitors (CMPs), whereas Ly-HSCs give rise to common lymphoid progenitors (CLPs). These CMPs and CLPs go on to generate most mature hematopoietic cell types, as indicated. Within the in vivo BM microenvironmental niche, Ly-HSCs are supported mainly by BMP signaling, whereas My-HSCs are regulated mainly by TGF-β signaling.

Figure 3.

Sources of transforming growth factor β (TGF-β) in the hematopoietic stem cell (HSC) and chronic myelogenous leukemia (CML) stem-cell niche in mice. Within the BM microenvironmental niche in mice, TGF-β is a key factor regulating the self-renewal capacity of both HSCs and CML stem cells. TGF-β produced in its latent form by HSCs is processed into its active form by adjacent nonmyelinating Schwann cells. Megakaryocytes are a source of TGF-β to maintain HSCs. This TGF-β may also support the self-renewal and quiescence of CML stem cells. Natural killer (NK) cells are a possible source of TGF-β driving the resistance of CML stem cells to tyrosine kinase inhibitors. Osteoclasts that resorb bone matrix and thus release stored TGF-β during bone regeneration may also contribute to self-renewal of CML stem cells.

Figure 4.

Transforming growth factor β (TGF-β) and Forkhead O (FOXO) signaling cooperate to ensure hematopoietic stem cell (HSC) quiescence. The activities of FOXO transcription factors lead to expression of the Cdkn1c gene encoding the CDK inhibitor p57^Kip2, which is essential for sustaining HSC quiescence. TGF-β signaling in the bone marrow (BM) niche induces p57^Kip2 expression in HSCs. Because TGF-β signaling activates Smad3, and Smad3 can associate with FOXO transcription factors to induce p57^Kip2 production, a functional axis that integrates TGF-β signaling through Smad3 and FOXO proteins may control HSC quiescence and maintenance.

Figure 5.

An “integrator” role for Smad3 in the maintenance of chronic myelogenous leukemia (CML) stemness. Smad3 participates in nutrient-activated p38 mitogen-activated protein kinase (MAPK) signaling that supports CML stem cell self-renewal and in TGF-β signaling that supports CML stem cell quiescence. The nutrient-activated p38 MAPK pathway phosphorylates Ser208 in the Smad3 linker region. Activated TβRI kinase phosphorylates Smad3 at the carboxy-terminal two-serine residues, which then controls stem-cell quiescence. CML stem cells show Smad3 phosphorylation at Ser208 in the linker region and at the carboxy-terminal serines. Posttranslational modification of Smad3 therefore integrates two intracellular pathways to regulate the self-renewal capacity and resistance of CML stem cells to tyrosine kinase inhibitors. Because nutrient-activated p38 MAPK–Smad3 signaling does not occur in normal hematopoietic stem cells (HSCs), inhibitors targeting this nutrient pathway might provide clinical benefits for CML patients.