Abstract
Abstract 954: TGF-ß signaling inhibition counteracts myelofibrosis in MPN
Cancer research (Chicago, Ill.), Vol.77(13_Supplement), pp.954-954
07/01/2017
DOI: 10.1158/1538-7445.AM2017-954
Abstract
Abstract Myelofibrosis (MF) is a common feature of the Philadelphia-Chromosome negative (Ph-) myeloproliferative neoplasms (MPN), a group that includes Primary Myelofibrosis (PMF), Essential Thrombocytosis (ET) and Polycythemia Vera (PV). Current treatment with Jak2 inhibitors reduces splenomegaly, but does not eliminate malignant clones nor improve bone marrow (BM) or spleen fibrosis, underlining the need for alternative therapies. One promising target is TGF-β1, a cytokine crucial for the development of myelofibrosis that is elevated in PMF patient plasma, progenitors and megakaryocytes (MK), and is known to promote fibrosis through stimulation of fibroblasts and their progenitors, mesenchymal stroma cells (MSC). Dysregulation of TGF-β1 signaling has been described in a number of mouse models of myelofibrosis exhibiting aberrant megakaryopoiesis, one of the hallmarks of MPNs. Preliminary data from 93 MPN patients showed overexpression of TGF-ß in PMF samples (p=0.001), with increased activation of the canonical target SMAD2 (p=0.005). We tested the efficacy of the orally available TGF-β1 signaling inhibitor Galunisertib (LY2157299) in counteracting fibrosis in two MF mouse models of common MPN oncogenes Jak2 and Mpn. Mice in the first model express the constitutively active human Jak2V617F mutant under the control of the ubiquitous hematopoietic promoter vav1 and show a PV-like phenotype at 6 weeks old, progressing to fibrosis of bone marrow (BM) and spleen around 25-30 weeks. Thirty week old mice were treated with Galunisertib for 4 weeks and showed a significant decrease in fibrosis compared to control mice. Similar results were observed in 50 week old mice treated with a murine antibody against TGFβRII (IMC-TR1,LY3022859) for 4 weeks.Our second model relies on transplantation of mice with BM cells transduced with MPLW515L, a mutant mpl variant that is active in the absence of TPO. These mice rapidly develop MF, myeloproliferation and splenomegaly. Flow cytometry showed an expansion of immature and mature megakaryocytes with overexpression of TGF-β1 in MPLW515L cells. Treatment from day 12 to day 26 after transplantation reduced both white blood cell counts (a measure of myeloproliferation) and fibrosis as measured by reticulin staining. In vitro, Galunisertib counteracted the pro-fibrotic effects of TGF-ß1 on both murine and human MSC by antagonizing its stimulatory effects on collagen I and III production. Analysis of MSCs from Galunisertib-treated mice also showed reduced collagen I and III production compared to controls. In conclusion, we offer further evidence that aberrant megakaryopoiesis drives TGF-β1 overproduction in MPN by increasing megakaryocyte numbers and overexpressing TGF-β1 in mutant MKs. Galunisertib counteracts TGF-ß1 induced fibrosis in two MPN mouse-models and is a promising candidate for symptomatic treatment of myelofibrosis. Citation Format: Matthias Bartenstein, Lanzhu Yue, Wanke Zhao, Wanting Tina Ho, Cem Murdun, Adam W. Mailloux, Ling Zhang, Anjali Budhakoti, Kith Pradhan, Franck Rapaport, Huaquan Wang, Zonghong Shao, Ulrich Steidl, Ross L. Levine, Zhizhuang Joe Zhao, Amit K. Verma, Pearlie K. Epling-Burnette. TGF-ß signaling inhibition counteracts myelofibrosis in MPN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 954. doi:10.1158/1538-7445.AM2017-954
Details
- Title: Subtitle
- Abstract 954: TGF-ß signaling inhibition counteracts myelofibrosis in MPN
- Creators
- Matthias Bartenstein - Albert Einstein College of MedicineLanzhu Yue - Moffitt Cancer CenterWanke Zhao - University of Oklahoma Health Sciences CenterWanting Tina Ho - University of Oklahoma Health Sciences CenterCem Murdun - Moffitt Cancer CenterAdam W. Mailloux - Moffitt Cancer CenterLing Zhang - Moffitt Cancer CenterAnjali Budhakoti - Albert Einstein College of MedicineKith Pradhan - Albert Einstein College of MedicineFranck Rapaport - Memorial Sloan Kettering Cancer CenterHuaquan Wang - Tianjin Medical University General HospitalZonghong Shao - Tianjin Medical University General HospitalUlrich Steidl - Albert Einstein College of MedicineRoss L. Levine - Memorial Sloan Kettering Cancer CenterZhizhuang Joe Zhao - University of Oklahoma Health Sciences CenterAmit K. Verma - Albert Einstein College of MedicinePearlie K. Epling-Burnette - Moffitt Cancer Center
- Resource Type
- Abstract
- Publication Details
- Cancer research (Chicago, Ill.), Vol.77(13_Supplement), pp.954-954
- DOI
- 10.1158/1538-7445.AM2017-954
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Language
- English
- Date published
- 07/01/2017
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984297520702771
Metrics
2 Record Views