title: Reduced SMAD7 leads to overactivation of TGF-beta signaling in MDS that can be reversed by a specific inhibitor of TGF-beta receptor I kinase.
abstract: Even though myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis, the molecular alterations that lead to marrow failure have not been well elucidated. We have previously shown that the myelosuppressive TGF-β pathway is constitutively activated in MDS progenitors. Because there is conflicting data about upregulation of extracellular TGF-β levels in MDS, we wanted to determine the molecular basis of TGF-β pathway overactivation and consequent hematopoietic suppression in this disease. We observed that SMAD7, a negative regulator of TGF-β receptor I (TBRI) kinase, is markedly decreased in a large meta-analysis of gene expression studies from MDS marrow-derived CD34(+) cells. SMAD7 protein was also found to be significantly decreased in MDS marrow progenitors when examined immunohistochemically in a bone marrow tissue microarray. Reduced expression of SMAD7 in hematopoietic cells led to increased TGF-β-mediated gene transcription and enhanced sensitivity to TGF-β-mediated suppressive effects. The increased TGF-β signaling due to SMAD7 reduction could be effectively inhibited by a novel clinically relevant TBRI (ALK5 kinase) inhibitor, LY-2157299. LY-2157299 could inhibit TGF-β-mediated SMAD2 activation and hematopoietic suppression in primary hematopoietic stem cells. Furthermore, in vivo administration of LY-2157299 ameliorated anemia in a TGF-β overexpressing transgenic mouse model of bone marrow failure. Most importantly, treatment with LY-2157199 stimulated hematopoiesis from primary MDS bone marrow specimens. These studies demonstrate that reduction in SMAD7 is a novel molecular alteration in MDS that leads to ineffective hematopoiesis by activating of TGF-β signaling in hematopoietic cells. These studies also illustrate the therapeutic potential of TBRI inhibitors in MDS.
authors.affiliation: Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.forename: Christine
authors.initials: C
authors.lastname: McMahon
authors.forename: Tushar
authors.initials: T
authors.lastname: Bhagat
authors.forename: Cristina
authors.initials: C
authors.lastname: Alencar
authors.forename: Yiting
authors.initials: Y
authors.lastname: Yu
authors.forename: Melissa
authors.initials: M
authors.lastname: Fazzari
authors.forename: Davendra
authors.initials: D
authors.lastname: Sohal
authors.forename: Christoph
authors.initials: C
authors.lastname: Heuck
authors.forename: Krishna
authors.initials: K
authors.lastname: Gundabolu
authors.forename: Chun
authors.initials: C
authors.lastname: Ng
authors.forename: Yongkai
authors.initials: Y
authors.lastname: Mo
authors.forename: Wa
authors.initials: W
authors.lastname: Shen
authors.forename: Amittha
authors.initials: A
authors.lastname: Wickrema
authors.forename: Guanghui
authors.initials: G
authors.lastname: Kong
authors.forename: Ellen
authors.initials: E
authors.lastname: Friedman
authors.forename: Lubomir
authors.initials: L
authors.lastname: Sokol
authors.forename: Ioannis
authors.initials: I
authors.lastname: Mantzaris
authors.forename: Giannis
authors.initials: G
authors.lastname: Mantzaris
authors.forename: Andrea
authors.initials: A
authors.lastname: Pellagatti
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Boultwood
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
authors.forename: Ulrich
authors.initials: U
authors.lastname: Steidl
authors.forename: Lei
authors.initials: L
authors.lastname: Yan
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Yingling
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lahn
authors.forename: Alan
authors.initials: A
authors.lastname: List
authors.forename: Markus
authors.initials: M
authors.lastname: Bitzer
authors.forename: Amit
authors.initials: A
authors.lastname: Verma
mesh_terms: D000740:Anemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051906:Smad7 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011804:Quinolines; D018125:Receptors, Transforming Growth Factor beta; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; C557799:LY-2157299; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse