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Role of transforming growth factor-β in hematologic malignancies

Mei Dong and Gerard C. Blobe

Article Figures & Data

Figures

  • 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.

Tables

  • Table 1.

    Altered TGF-β signaling in hematalogic malignancies

    Disease and alterations in the TGF-β signaling pathwayReference
    AML-M2
        AML1/ETO blocks Smad3 DNA binding Jakubowiak et al47
    AML-M3
        PML-RARα blocks phosphorylation of Smad2/3 Lin et al49
    AML
        Dominant negative mutations in Smad4 Imai et al50
        Hypomorphic TβRI polymorphism, TβRI(6A) Pasche et al51
    CML
        Evi-1 overexpression blocks Smad3 DNA binding, recruits corepressor Kurokawa et al43
        AML1/EVI-1 blocks Smad3 DNA binding, recruits corepressor Kurokawa et al54
    Childhood T-cell ALL
        Decreased Smad3 protein expression Wolfraim et al55
    Adult T-cell ALL
        HTLV-1 Tax inhibits coactivator CBP/p300, blocks Smad2/3/4 formation, inhibits Smad3 DNA binding Mori et al44, Lee et al56, Arnulf et al57
    CLL
        Decreased TβRI expression DeCoteau et al74, Lagneaux et al84
        TβRI mutation (Leu12Gln with single in-frame Ala deletion) Schiemann et al75
        Increased TβRIII expression Klein et al12, Jelinkek et al13
    Hairy-cell leukemia
        Increased TGF-β production enhances bone marrow fibrosis Shehata et al76
    Polycythemia vera
        Decreased TβRII expression Rooke et al61
    Essential thrombocythemia
        Decreased Smad4 expression Kuroda et al60
        Decreased TβRII expression Rooke et al61
    NHL
        Reduced TβRI and TβRII expression Capocasale et al66, Schiemann et al69
        Dominant negative mutation of TβRII (D404G) Knaus et al67
    Multiple myeloma
        Deficient trafficking of TGF-β receptors to the cell surface Fernandez et al83
    • TGF-β indicates transforming growth factor-β.