The role of TGFβ in hematopoiesis and myeloid disorders

Abstract

The role of transforming growth factor-β (TGFβ) signaling in embryological development and tissue homeostasis has been thoroughly characterized. Its canonical downstream cascade is well known, even though its true complexity and other non-canonical pathways are still being explored. TGFβ signaling has been described as an important pathway involved in carcinogenesis and cancer progression. In the hematopoietic compartment, the TGFβ pathway is an important regulator of proliferation and differentiation of different cell types and has been implicated in the pathogenesis of a diverse variety of bone marrow disorders. Due to its importance in hematological diseases, novel inhibitors of this pathway are being developed against a number of hematopoietic disorders, including myelodysplastic syndromes (MDS). In this review, we provide an overview of the TGFβ pathway, focusing on its role in hematopoiesis and impact on myeloid disorders. We will discuss therapeutic interventions with promising results against MDS.

TGFβ ligands are released at the extracellular space, triggering the TGFb receptor in a dimeric structure (1). Some TGFb receptors need the presence of co-receptors (such as betaglycan) to facilitate the activation (2). After being activated, the TGFβ receptor I phosphorylates R-SMAD proteins (SMAD2/SMAD3 or SMAD 1/SMAD5/SMAD8), activating the canonical pathway (4). Some proteins enhance this phosphorylation (SARA), but inhibitors (e.g., BAMBI or FKBP12) can prevent it (3). SMAD7 is an inhibitory SMAD that prevents the downstream activation of the SMAD pathway (6). After being phosphorylated, R-SMAD binds to SMAD4 (5) and translocates to the nucleus, recruiting diverse transcriptional factors and enhancing specific genetic expression (7). Besides the canonical pathway, the TGFb receptor can activate non-SMAD, non-canonical signaling pathways, such as MAPK, PI3KAKT, or Rho pathways (8) that can modulate SMAD downstream regulation and modify transcriptional patterns (9)

Role of TGFβ in the different hematopoietic lineages. HSC hematopoietic stem cell, EMkP erythroid-megakaryocyte progenitor, GMP granulocyte-monocyte progenitor, CFU-M colony- forming unit monocyte. CFU-G colony-forming unit granulocyte

Ineffective erythropoiesis in myelodysplastic syndromes and effects of TGFβ modulation. Genomic, epigenetic and microenvironment factors induce functional abnormalities in hematopoietic stem cells and progenitors, leading to early erythroid apoptosis and ineffective erythropoiesis with the absence of late-terminal erythroid differentiation. This is further enhanced by SMAD2/3 signaling via TGFβ activation. Inhibition of TGFβ signaling may partially restore the differentiation block and confer increased fitness to erythroid precursors, leading to late-terminal erythroid differentiation and hematological improvement. BFUE burst-forming unit erythroid progenitor, CFU-E colony-forming unit erythroid progenitor, ProEB proerythroblast, BasoEB basophilic erythroblast, PolyEB polyorthochromatic erythroblast, OrthoEB orthochromatic erythroblast