TY - JOUR
T1 - TGFβR-SMAD3 Signaling Induces Resistance to PARP Inhibitors in the Bone Marrow Microenvironment
AU - Le, Bac Viet
AU - Podszywalow-Bartnicka, Paulina
AU - Maifrede, Silvia
AU - Sullivan-Reed, Katherine
AU - Nieborowska-Skorska, Margaret
AU - Golovine, Konstantin
AU - Yao, Juo Chin
AU - Nejati, Reza
AU - Cai, Kathy Q.
AU - Caruso, Lisa Beatrice
AU - Swatler, Julian
AU - Dabrowski, Michal
AU - Lian, Zhaorui
AU - Valent, Peter
AU - Paietta, Elisabeth M.
AU - Levine, Ross L.
AU - Fernandez, Hugo F.
AU - Tallman, Martin S.
AU - Litzow, Mark R.
AU - Huang, Jian
AU - Challen, Grant A.
AU - Link, Daniel
AU - Tempera, Italo
AU - Wasik, Mariusz A.
AU - Piwocka, Katarzyna
AU - Skorski, Tomasz
N1 - Funding Information:
This work was funded by NIH R01CA186238 , R01CA244044 , and R01CA247707 ; the Leukemia and Lymphoma Society Translational Research Program award 6565-19 ; and the When Everyone Survives Foundation (to T.S.). B.V.L. has been supported by the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant agreement no. 665735 and by the funding from Polish Ministry of Science and Higher Education funds for the implementation of international projects, 2016–2020 (to K.P.). K.S.-R. was supported by T32CA009009035-43 from NIH . P.P.-B. has been supported by the Hollis Brownstein New Investigator Research Grant from the Leukemia Research Foundation (funding cycle 2018–2019) and research grants from the National Science Centre ( 2014/15/D/NZ3/05187 and 2018/30/M/NZ3/00274 ). P.V. was supported by the Austrian Science Fund (FWF) research grants F4701-B28 and F4704-B28 . We thank the Laboratory of Animal Models, Nencki Institute of Experimental Biology, Warsaw for the generation of lentivirally transferred MV4-11 cells. This work was supported by the ANIMOD project within the Team Tech Core Facility Plus program of the Foundation for Polish Science , co-financed by the European Union under the European Regional Development Fund .
Funding Information:
This work was funded by NIH R01CA186238, R01CA244044, and R01CA247707; the Leukemia and Lymphoma Society Translational Research Program award 6565-19; and the When Everyone Survives Foundation (to T.S.). B.V.L. has been supported by the European Union's Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant agreement no. 665735 and by the funding from Polish Ministry of Science and Higher Education funds for the implementation of international projects, 2016?2020 (to K.P.). K.S.-R. was supported by T32CA009009035-43 from NIH. P.P.-B. has been supported by the Hollis Brownstein New Investigator Research Grant from the Leukemia Research Foundation (funding cycle 2018?2019) and research grants from the National Science Centre (2014/15/D/NZ3/05187 and 2018/30/M/NZ3/00274). P.V. was supported by the Austrian Science Fund (FWF) research grants F4701-B28 and F4704-B28. We thank the Laboratory of Animal Models, Nencki Institute of Experimental Biology, Warsaw for the generation of lentivirally transferred MV4-11 cells. This work was supported by the ANIMOD project within the Team Tech Core Facility Plus program of the Foundation for Polish Science, co-financed by the European Union under the European Regional Development Fund. B.V.L. P.P.-B. S.M. K.S.-R. M.N.-S. K.G. J.-C.Y. R.N. K.Q.C. J.S. M.D. and Z.L. performed the experiments. E.M.P. provided the genetically characterized AML samples from E1900, and R.L.L. performed the somatic sequencing studies of the E1900 samples. H.F.F. led trial E1900, M.S.T. was the ECOG-ACRIN Leukemia Committee chair when E1900 was activated, and M.R.L. is the current ECOG-ACRIN Leukemia Committee chair. P.V. provided the genetically characterized AML samples. G.A.C. and D.L. provided the genetically modified mice. J.H. supervised Z.L. M.A.W. supervised R.N. and K.Q.C. and critically reviewed the manuscript. T.S. and K.P. designed the studies, supervised the experiments, and wrote the manuscript. The authors declare no competing interests.
Publisher Copyright:
© 2020 The Author(s)
PY - 2020/10/6
Y1 - 2020/10/6
N2 - Le et al. show that the TGF-β1-TGFβR kinase-SMAD3 pathway protects leukemia cells from PARP inhibitor (PARPi)-mediated synthetic lethality in the bone marrow microenvironment. The targeting of the TGF-β1 axis restored the sensitivity of leukemia cells to PARPi and prolonged survival of leukemia-bearing mice.
AB - Le et al. show that the TGF-β1-TGFβR kinase-SMAD3 pathway protects leukemia cells from PARP inhibitor (PARPi)-mediated synthetic lethality in the bone marrow microenvironment. The targeting of the TGF-β1 axis restored the sensitivity of leukemia cells to PARPi and prolonged survival of leukemia-bearing mice.
KW - PARP inhibitor resistance
KW - TGFβR signaling
KW - bone marrow microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85092277361&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2020.108221
DO - 10.1016/j.celrep.2020.108221
M3 - Article
C2 - 33027668
AN - SCOPUS:85092277361
SN - 2211-1247
VL - 33
JO - Cell Reports
JF - Cell Reports
IS - 1
M1 - 108221
ER -