CSF1R inhibitors exhibit antitumor activity in acute myeloid leukemia by blocking paracrine signals from support cells

David K. Edwards, Kevin Watanabe-Smith, Angela Rofelty, Alisa Damnernsawad, Ted Laderas, Adam Lamble, Evan Lind, Andy Kaempf, Motomi (Tomi) Mori, Mara Rosenberg, Amanda d’Almeida, Nicola Long, Anupriya Agarwal, David Tyler Sweeney, Marc Loriaux, Shannon McWeeney, Jeffrey Tyner

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)588-599
Number of pages12
JournalBlood
Volume133
Issue number6
DOIs
StatePublished - Feb 7 2019

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Hepatocyte Growth Factor
Acute Myeloid Leukemia
Macrophage Colony-Stimulating Factor
Cytokines
Cells
Colony-Stimulating Factor Receptors
Flow cytometry
Receptor Protein-Tyrosine Kinases
Conditioned Culture Medium
Survival
Small Interfering RNA
Myeloid Cells
5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine
Intercellular Signaling Peptides and Proteins
Cell Survival
Flow Cytometry
Leukemia
Ligands
Therapeutics
Tissue Donors

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

CSF1R inhibitors exhibit antitumor activity in acute myeloid leukemia by blocking paracrine signals from support cells. / Edwards, David K.; Watanabe-Smith, Kevin; Rofelty, Angela; Damnernsawad, Alisa; Laderas, Ted; Lamble, Adam; Lind, Evan; Kaempf, Andy; Mori, Motomi (Tomi); Rosenberg, Mara; d’Almeida, Amanda; Long, Nicola; Agarwal, Anupriya; Sweeney, David Tyler; Loriaux, Marc; McWeeney, Shannon; Tyner, Jeffrey.

In: Blood, Vol. 133, No. 6, 07.02.2019, p. 588-599.

Research output: Contribution to journalArticle

Edwards, DK, Watanabe-Smith, K, Rofelty, A, Damnernsawad, A, Laderas, T, Lamble, A, Lind, E, Kaempf, A, Mori, MT, Rosenberg, M, d’Almeida, A, Long, N, Agarwal, A, Sweeney, DT, Loriaux, M, McWeeney, S & Tyner, J 2019, 'CSF1R inhibitors exhibit antitumor activity in acute myeloid leukemia by blocking paracrine signals from support cells', Blood, vol. 133, no. 6, pp. 588-599. https://doi.org/10.1182/blood-2018-03-838946
Edwards DK, Watanabe-Smith K, Rofelty A, Damnernsawad A, Laderas T, Lamble A et al. CSF1R inhibitors exhibit antitumor activity in acute myeloid leukemia by blocking paracrine signals from support cells. Blood. 2019 Feb 7;133(6):588-599. https://doi.org/10.1182/blood-2018-03-838946
Edwards, David K. ; Watanabe-Smith, Kevin ; Rofelty, Angela ; Damnernsawad, Alisa ; Laderas, Ted ; Lamble, Adam ; Lind, Evan ; Kaempf, Andy ; Mori, Motomi (Tomi) ; Rosenberg, Mara ; d’Almeida, Amanda ; Long, Nicola ; Agarwal, Anupriya ; Sweeney, David Tyler ; Loriaux, Marc ; McWeeney, Shannon ; Tyner, Jeffrey. / CSF1R inhibitors exhibit antitumor activity in acute myeloid leukemia by blocking paracrine signals from support cells. In: Blood. 2019 ; Vol. 133, No. 6. pp. 588-599.
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AU - Edwards, David K.

AU - Watanabe-Smith, Kevin

AU - Rofelty, Angela

AU - Damnernsawad, Alisa

AU - Laderas, Ted

AU - Lamble, Adam

AU - Lind, Evan

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

AU - Tyner, Jeffrey

PY - 2019/2/7

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