TY - JOUR
T1 - CSF1R inhibitors exhibit antitumor activity in acute myeloid leukemia by blocking paracrine signals from support cells
AU - Edwards, David K.
AU - Watanabe-Smith, Kevin
AU - Rofelty, Angela
AU - Damnernsawad, Alisa
AU - Laderas, Ted
AU - Lamble, Adam
AU - Lind, Evan F.
AU - Kaempf, Andy
AU - Mori, Motomi (Tomi)
AU - Rosenberg, Mara
AU - d’Almeida, Amanda
AU - Long, Nicola
AU - Agarwal, Anupriya
AU - Sweeney, David Tyler
AU - Loriaux, Marc
AU - McWeeney, Shannon K.
AU - Tyner, Jeffrey W.
N1 - Funding Information:
The authors thank Patrice Lee and David Chantry of Array BioPharma for providing ARRY-382, Mandy Gilchrist and Brianna Garcia from the OHSU Flow Cytometry Core for technical assistance, Daniel Bottomly and Beth Wilmot for conducting Beat AML exome sequencing, and Cristina Tognon and Elie Traer for assistance with Beat AML patient samples. Additionally, the authors thank Stephen Kurtz, Christopher Eide, Quinn Roth-Carter, Riley Roth-Carter, and Chris Cheng. This work was supported by The Leukemia & Lymphoma Society. J.W.T. received grants from the V Foundation for Cancer Research, the Gabrielle’s Angel Foundation for Cancer Research, and the National Institutes of Health National Cancer Institute (1R01CA183947, 1U01CA217862, 1U01CA214116, and 1U54CA224019). D.K.E. was supported by the National Science Foundation Graduate Research Fellowship Program (DGE-1448072).
Funding Information:
This work was supported by The Leukemia & Lymphoma Society. J.W.T. received grants from the V Foundation for Cancer Research, the Gabrielle’s Angel Foundation for Cancer Research, and the National Institutes of Health National Cancer Institute (1R01CA183947, 1U01CA217862, 1U01CA214116, and 1U54CA224019). D.K.E. was supported by the National Science Foundation Graduate Research Fellowship Program (DGE-1448072).
Publisher Copyright:
© 2019 by The American Society of Hematology.
PY - 2019/2/7
Y1 - 2019/2/7
N2 - To identify new therapeutic targets in acute myeloid leukemia (AML), we performed small-molecule and small-interfering RNA (siRNA) screens of primary AML patient samples. In 23% of samples, we found sensitivity to inhibition of colony-stimulating factor 1 (CSF1) receptor (CSF1R), a receptor tyrosine kinase responsible for survival, proliferation, and differentiation of myeloid-lineage cells. Sensitivity to CSF1R inhibitor GW-2580 was found preferentially in de novo and favorable-risk patients, and resistance to GW-2580 was associated with reduced overall survival. Using flow cytometry, we discovered that CSF1R is not expressed on the majority of leukemic blasts but instead on a subpopulation of supportive cells. Comparison of CSF1R-expressing cells in AML vs healthy donors by mass cytometry revealed expression of unique cell-surface markers. The quantity of CSF1R-expressing cells correlated with GW-2580 sensitivity. Exposure of primary AML patient samples to a panel of recombinant cytokines revealed that CSF1R inhibitor sensitivity correlated with a growth response to CSF1R ligand, CSF1, and other cytokines, including hepatocyte growth factor (HGF). The addition of CSF1 increased the secretion of HGF and other cytokines in conditioned media from AML patient samples, whereas adding GW-2580 reduced their secretion. In untreated cells, HGF levels correlated significantly with GW-2580 sensitivity. Finally, recombinant HGF and HS-5–conditioned media rescued cell viability after GW-2580 treatment in AML patient samples. Our results suggest that CSF1R-expressing cells support the bulk leukemia population through the secretion of HGF and other cytokines. This study identifies CSF1R as a novel therapeutic target of AML and provides a mechanism of paracrine cytokine/growth factor signaling in this disease.
AB - To identify new therapeutic targets in acute myeloid leukemia (AML), we performed small-molecule and small-interfering RNA (siRNA) screens of primary AML patient samples. In 23% of samples, we found sensitivity to inhibition of colony-stimulating factor 1 (CSF1) receptor (CSF1R), a receptor tyrosine kinase responsible for survival, proliferation, and differentiation of myeloid-lineage cells. Sensitivity to CSF1R inhibitor GW-2580 was found preferentially in de novo and favorable-risk patients, and resistance to GW-2580 was associated with reduced overall survival. Using flow cytometry, we discovered that CSF1R is not expressed on the majority of leukemic blasts but instead on a subpopulation of supportive cells. Comparison of CSF1R-expressing cells in AML vs healthy donors by mass cytometry revealed expression of unique cell-surface markers. The quantity of CSF1R-expressing cells correlated with GW-2580 sensitivity. Exposure of primary AML patient samples to a panel of recombinant cytokines revealed that CSF1R inhibitor sensitivity correlated with a growth response to CSF1R ligand, CSF1, and other cytokines, including hepatocyte growth factor (HGF). The addition of CSF1 increased the secretion of HGF and other cytokines in conditioned media from AML patient samples, whereas adding GW-2580 reduced their secretion. In untreated cells, HGF levels correlated significantly with GW-2580 sensitivity. Finally, recombinant HGF and HS-5–conditioned media rescued cell viability after GW-2580 treatment in AML patient samples. Our results suggest that CSF1R-expressing cells support the bulk leukemia population through the secretion of HGF and other cytokines. This study identifies CSF1R as a novel therapeutic target of AML and provides a mechanism of paracrine cytokine/growth factor signaling in this disease.
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U2 - 10.1182/blood-2018-03-838946
DO - 10.1182/blood-2018-03-838946
M3 - Article
C2 - 30425048
AN - SCOPUS:85061158772
SN - 0006-4971
VL - 133
SP - 588
EP - 599
JO - Blood
JF - Blood
IS - 6
ER -