Role of transforming growth factor-beta in hematologic malignancies

Abstract

The transforming growth factor-beta (TGF-beta) signaling pathway is an essential regulator of cellular processes, including proliferation, differentiation, migration, and cell survival. During hematopoiesis, the TGF-beta signaling pathway is a potent negative regulator of proliferation while stimulating differentiation and apoptosis when appropriate. In hematologic malignancies, including leukemias, myeloproliferative disorders, lymphomas, and multiple myeloma, resistance to these homeostatic effects of TGF-beta develops. Mechanisms for this resistance include mutation or deletion of members of the TGF-beta signaling pathway and disruption of the pathway by oncoproteins. These alterations define a tumor suppressor role for the TGF-beta pathway in human hematologic malignancies. On the other hand, elevated levels of TGF-beta can promote myelofibrosis and the pathogenesis of some hematologic malignancies through their effects on the stroma and immune system. Advances in the TGF-beta signaling field should enable targeting of the TGF-beta signaling pathway for the treatment of hematologic malignancies.

Figure 1.

The TGF-β signaling pathway and mechanisms of inhibition during leukemogenesis. TGF-β binds TβRII, directly or through TβRIII, inducing association of TβRII with TβRI. TβRII then phosphorylates and activates TβRI, which then phosphorylates Smad2 or Smad3. SARA acts to concentrate Smad2/3 near the cell surface, facilitating their phosphorylation by TβRI. Phosphorylated Smad2/3 associate with Smad4 and translocate into the nucleus, where they activate transcription of target genes. Smad7 inhibits TGF-β signaling by preventing TβRI's activation of Smad2/3. In leukemias, disease-specific oncoproteins disrupt this pathway through different mechanisms. PML-RARα prevents the phosphorylation of Smad2/3 by interrupting the formation of TGF-β receptor/SARA/Smad complexes. AML/ETO, AML/EVI-1, and Evi-1 inhibit Smad3 DNA binding and recruit the transcription repressor, CtBP. Tax disrupts the interaction of Smads with the transcriptional coactivator CBP/p300 and blocks the formation of Smad2/3/4 complexes.