Efficacy of ALK5 inhibition in myelofibrosis

Lanzhu Yue, Matthias Bartenstein, Wanke Zhao, Wanting Tina Ho, Ying Han, Cem Murdun, Adam W. Mailloux, Ling Zhang, Xuefeng Wang, Anjali Budhathoki, Kith Pradhan, Franck Rapaport, Huaquan Wang, Zonghong Shao, Xiubao Ren, Ulrich G. Steidl, Ross L. Levine, Zhizhuang Joe Zhao, Amit K. Verma, Pearlie K. Epling-Burnette

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2, MPL, and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-β family members are profibrotic cytokines and we observed significant TGF-β1 isoform overexpression in a large cohort of primary MF patient samples. Significant overexpression of TGF-β1 was also observed in murine clonal MPLW515L megakaryocytic cells. TGF-β1 stimulated the deposition of excessive collagen by mesenchymal stromal cells (MSCs) by activating the TGF-β receptor I kinase (ALK5)/Smad3 pathway. MSCs derived from MPLW515L mice demonstrated sustained overproduction of both collagen I and collagen III, effects that were abrogated by ALK5 inhibition in vitro and in vivo. Importantly, use of galunisertib, a clinically active ALK5 inhibitor, significantly improved MF in both MPLW515L and JAK2V617F mouse models. These data demonstrate the role of malignant hematopoietic stem cell (HSC)/TGF-β/MSC axis in the pathogenesis of MF, and provide a preclinical rationale for ALK5 blockade as a therapeutic strategy in MF.

Original languageEnglish (US)
Pages (from-to)e90932
JournalJCI insight
Volume2
Issue number7
DOIs
StatePublished - Apr 6 2017

Fingerprint

Primary Myelofibrosis
Mesenchymal Stromal Cells
Collagen
LY-2157299
Extramedullary Hematopoiesis
Cytokines
Hematopoietic Stem Cells
Inhibition (Psychology)
Protein Isoforms
Phosphotransferases
Bone Marrow
Mutation

Cite this

Yue, L., Bartenstein, M., Zhao, W., Ho, W. T., Han, Y., Murdun, C., ... Epling-Burnette, P. K. (2017). Efficacy of ALK5 inhibition in myelofibrosis. JCI insight, 2(7), e90932. https://doi.org/10.1172/jci.insight.90932

Efficacy of ALK5 inhibition in myelofibrosis. / Yue, Lanzhu; Bartenstein, Matthias; Zhao, Wanke; Ho, Wanting Tina; Han, Ying; Murdun, Cem; Mailloux, Adam W.; Zhang, Ling; Wang, Xuefeng; Budhathoki, Anjali; Pradhan, Kith; Rapaport, Franck; Wang, Huaquan; Shao, Zonghong; Ren, Xiubao; Steidl, Ulrich G.; Levine, Ross L.; Zhao, Zhizhuang Joe; Verma, Amit K.; Epling-Burnette, Pearlie K.

In: JCI insight, Vol. 2, No. 7, 06.04.2017, p. e90932.

Research output: Contribution to journalArticle

Yue, L, Bartenstein, M, Zhao, W, Ho, WT, Han, Y, Murdun, C, Mailloux, AW, Zhang, L, Wang, X, Budhathoki, A, Pradhan, K, Rapaport, F, Wang, H, Shao, Z, Ren, X, Steidl, UG, Levine, RL, Zhao, ZJ, Verma, AK & Epling-Burnette, PK 2017, 'Efficacy of ALK5 inhibition in myelofibrosis', JCI insight, vol. 2, no. 7, pp. e90932. https://doi.org/10.1172/jci.insight.90932
Yue L, Bartenstein M, Zhao W, Ho WT, Han Y, Murdun C et al. Efficacy of ALK5 inhibition in myelofibrosis. JCI insight. 2017 Apr 6;2(7):e90932. https://doi.org/10.1172/jci.insight.90932
Yue, Lanzhu ; Bartenstein, Matthias ; Zhao, Wanke ; Ho, Wanting Tina ; Han, Ying ; Murdun, Cem ; Mailloux, Adam W. ; Zhang, Ling ; Wang, Xuefeng ; Budhathoki, Anjali ; Pradhan, Kith ; Rapaport, Franck ; Wang, Huaquan ; Shao, Zonghong ; Ren, Xiubao ; Steidl, Ulrich G. ; Levine, Ross L. ; Zhao, Zhizhuang Joe ; Verma, Amit K. ; Epling-Burnette, Pearlie K. / Efficacy of ALK5 inhibition in myelofibrosis. In: JCI insight. 2017 ; Vol. 2, No. 7. pp. e90932.
@article{1dcd9bbf729a403fac4592b0bad77e55,
title = "Efficacy of ALK5 inhibition in myelofibrosis",
abstract = "Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2, MPL, and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-β family members are profibrotic cytokines and we observed significant TGF-β1 isoform overexpression in a large cohort of primary MF patient samples. Significant overexpression of TGF-β1 was also observed in murine clonal MPLW515L megakaryocytic cells. TGF-β1 stimulated the deposition of excessive collagen by mesenchymal stromal cells (MSCs) by activating the TGF-β receptor I kinase (ALK5)/Smad3 pathway. MSCs derived from MPLW515L mice demonstrated sustained overproduction of both collagen I and collagen III, effects that were abrogated by ALK5 inhibition in vitro and in vivo. Importantly, use of galunisertib, a clinically active ALK5 inhibitor, significantly improved MF in both MPLW515L and JAK2V617F mouse models. These data demonstrate the role of malignant hematopoietic stem cell (HSC)/TGF-β/MSC axis in the pathogenesis of MF, and provide a preclinical rationale for ALK5 blockade as a therapeutic strategy in MF.",
author = "Lanzhu Yue and Matthias Bartenstein and Wanke Zhao and Ho, {Wanting Tina} and Ying Han and Cem Murdun and Mailloux, {Adam W.} and Ling Zhang and Xuefeng Wang and Anjali Budhathoki and Kith Pradhan and Franck Rapaport and Huaquan Wang and Zonghong Shao and Xiubao Ren and Steidl, {Ulrich G.} and Levine, {Ross L.} and Zhao, {Zhizhuang Joe} and Verma, {Amit K.} and Epling-Burnette, {Pearlie K.}",
year = "2017",
month = "4",
day = "6",
doi = "10.1172/jci.insight.90932",
language = "English (US)",
volume = "2",
pages = "e90932",
journal = "JCI insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "7",

}

TY - JOUR

T1 - Efficacy of ALK5 inhibition in myelofibrosis

AU - Yue, Lanzhu

AU - Bartenstein, Matthias

AU - Zhao, Wanke

AU - Ho, Wanting Tina

AU - Han, Ying

AU - Murdun, Cem

AU - Mailloux, Adam W.

AU - Zhang, Ling

AU - Wang, Xuefeng

AU - Budhathoki, Anjali

AU - Pradhan, Kith

AU - Rapaport, Franck

AU - Wang, Huaquan

AU - Shao, Zonghong

AU - Ren, Xiubao

AU - Steidl, Ulrich G.

AU - Levine, Ross L.

AU - Zhao, Zhizhuang Joe

AU - Verma, Amit K.

AU - Epling-Burnette, Pearlie K.

PY - 2017/4/6

Y1 - 2017/4/6

N2 - Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2, MPL, and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-β family members are profibrotic cytokines and we observed significant TGF-β1 isoform overexpression in a large cohort of primary MF patient samples. Significant overexpression of TGF-β1 was also observed in murine clonal MPLW515L megakaryocytic cells. TGF-β1 stimulated the deposition of excessive collagen by mesenchymal stromal cells (MSCs) by activating the TGF-β receptor I kinase (ALK5)/Smad3 pathway. MSCs derived from MPLW515L mice demonstrated sustained overproduction of both collagen I and collagen III, effects that were abrogated by ALK5 inhibition in vitro and in vivo. Importantly, use of galunisertib, a clinically active ALK5 inhibitor, significantly improved MF in both MPLW515L and JAK2V617F mouse models. These data demonstrate the role of malignant hematopoietic stem cell (HSC)/TGF-β/MSC axis in the pathogenesis of MF, and provide a preclinical rationale for ALK5 blockade as a therapeutic strategy in MF.

AB - Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2, MPL, and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-β family members are profibrotic cytokines and we observed significant TGF-β1 isoform overexpression in a large cohort of primary MF patient samples. Significant overexpression of TGF-β1 was also observed in murine clonal MPLW515L megakaryocytic cells. TGF-β1 stimulated the deposition of excessive collagen by mesenchymal stromal cells (MSCs) by activating the TGF-β receptor I kinase (ALK5)/Smad3 pathway. MSCs derived from MPLW515L mice demonstrated sustained overproduction of both collagen I and collagen III, effects that were abrogated by ALK5 inhibition in vitro and in vivo. Importantly, use of galunisertib, a clinically active ALK5 inhibitor, significantly improved MF in both MPLW515L and JAK2V617F mouse models. These data demonstrate the role of malignant hematopoietic stem cell (HSC)/TGF-β/MSC axis in the pathogenesis of MF, and provide a preclinical rationale for ALK5 blockade as a therapeutic strategy in MF.

UR - http://www.scopus.com/inward/record.url?scp=85043508838&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85043508838&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.90932

DO - 10.1172/jci.insight.90932

M3 - Article

C2 - 28405618

AN - SCOPUS:85043508838

VL - 2

SP - e90932

JO - JCI insight

JF - JCI insight

SN - 2379-3708

IS - 7

ER -