Transforming growth factor-ß (TGF-ß) signaling in hematopoiesis and tumorigenesis

Transforming growth factor β (TGF-β) signaling regulates numerous cellular and
physiological processes. Dysfunction of components of this signaling pathway leads to
a wide range of diseases ranging from malignant hematopoiesis, cardiovascular disease,
immunity abnormalities, connective tissue disease, reproductive disorders, metabolic
disorders, skeleton and muscular disorders, to developmental defects.
We focused on the role of Smad4 and TBRII genes in the hematopoiesis and studied a
conditional Smad4 knockout mouse. Mice with homozygous Smad4 deletion (Smad4Δ/Δ)
developed severe anemia 6-8 weeks after induction (mean hemoglobin 70g/L). The
anemia was not transplantable, as wild type mice reconstituted with Smad4Δ/Δ bone
marrow cells had normal peripheral blood counts. In contrast, lethally irradiated
Smad4Δ/Δ mice transplanted with wild type bone marrow cells developed anemia similar
to non-transplanted Smad4Δ/Δ mice. Liver iron stores were decreased and blood was
present in stool, indicating that the anemia was due to blood loss. Multiple polyps in
stomach and colon represent a likely source of the bleeding. We conclude that Smad4 is
not required for adult erythropoiesis and that anemia is solely the consequence of blood
loss. Regulation of hepcidin related genes (Atoh8, Id1 and Bmp6) responded to acute
bleeding in the absence of Smad4, TBRII and/or histone deacetylase 1 (HDAC1) genes. Smad4Δ/Δ mice did not develop an inflammatory disease typical for mice deficient in
TGF-b receptors I and II (TBRI and TBRII), suggesting that suppression of
inflammation by TGF-β is Smad4 independent. The same results were obtained when
Smad4 alleles were deleted selectively in hematopoietic cells using the VavCre
transgenic mice. Mice with a double knockout (Smad4Δ/Δ and TBRIIΔ/Δ) did not display
the TBRIIΔ/Δ -driven lethal inflammation suggesting that Smad4 signaling is required to
mediate the inflammatory phenotype. Smad4/TBRII was dispensable for the
megakaryopoiesis and erythropoiesis. Finally, we confirmed that the Smad4-signaling
pathway is required to suppress tumorigenesis in the gastrointestinal tract and loss of
Smad4-signaling in hematopoietic cells is sufficient to cause polyp formation in the gut.