The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
JAK–STAT Pathway Activation in Malignant and Nonmalignant Cells Contributes to MPN Pathogenesis and Therapeutic Response
Open accessAbstract
The identification of JAK2/MPL mutations in patients with myeloproliferative neoplasms (MPN) has led to the clinical development of JAK kinase inhibitors, including ruxolitinib. Ruxolitinib reduces splenomegaly and systemic symptoms in myelofibrosis and improves overall survival; however, the mechanism by which JAK inhibitors achieve efficacy has not been delineated. Patients with MPN present with increased levels of circulating proinflammatory cytokines, which are mitigated by JAK inhibitor therapy. We sought to elucidate mechanisms by which JAK inhibitors attenuate cytokine-mediated pathophysiology. Single-cell profiling demonstrated that hematopoietic cells from myelofibrosis models and patient samples aberrantly secrete inflammatory cytokines. Pan-hematopoietic Stat3 deletion reduced disease severity and attenuated cytokine secretion, with similar efficacy as observed with ruxolitinib therapy. In contrast, Stat3 deletion restricted to MPN cells did not reduce disease severity or cytokine production. Consistent with these observations, we found that malignant and nonmalignant cells aberrantly secrete cytokines and JAK inhibition reduces cytokine production from both populations. Significance: Our results demonstrate that JAK–STAT3-mediated cytokine production from malignant and nonmalignant cells contributes to MPN pathogenesis and that JAK inhibition in both populations is required for therapeutic efficacy. These findings provide novel insight into the mechanisms by which JAK kinase inhibition achieves therapeutic efficacy in MPNs. Cancer Discov; 5(3); 316–31. ©2015 AACR. See related commentary by Belver and Ferrando, p. 234 This article is highlighted in the In This Issue feature, p. 213
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Cites
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“Single-Cell Cytokine Secretion Assay A highdensity antibody barcode was created using a microchan nelguided flow patterning technique as previously described (16, 17).”
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Cited by
Spivak, J. L. (2017) · New England Journal of Medicine · doi:10.1056/nejmra1406186 · Cited by 404
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“Bone marrow fibrosis is a shared feature of all MPNs, but is the defining histopathological feature of PMF, a major diagnostic criterion (Zahr et al., 2016), and has been associated with poor outcomes (Kuter et al., 2007; Byrne et al., 2018).”
BackgroundInfluentialKleppe, M., Koche, R., Zou, L., van Galen, P., Hill, C. E., Dong, L., De Groote, S., Papalexi, E., Hanasoge Somasundara, A. V., Cordner, K., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2017.11.009 · Cited by 279
Self-citationReilley, M. J., McCoon, P., Cook, C., Lyne, P., Kurzrock, R., Kim, Y., Woessner, R., Younes, A., Nemunaitis, J., Fowler, N., et al. (2018) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-018-0436-5 · Cited by 245
Van Egeren, D., Escabi, J., Nguyen, M., Liu, S., Reilly, C. R., Patel, S., Kamaz, B., Kalyva, M., DeAngelo, D. J., Galinsky, I., et al. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2021.02.001 · Cited by 206
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Metadata
- Authors
- Kleppe, M., Kwak, M., Koppikar, P., Riester, M., Keller, M., Bastian, L., Hricik, T., Bhagwat, N., McKenney, A. S., Papalexi, E., Abdel-Wahab, O., Rampal, R., Marubayashi, S., Chen, J. J., Romanet, V., Fridman, J. S., Bromberg, J., Teruya-Feldstein, J., Murakami, M., Radimerski, T., Michor, F., Fan, R., & Levine, R. L.
- Venue
- Cancer Discovery
- Published
- 2015-03-01
- Volume
- 5
- Issue
- 3
- Pages
- 316-331
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2143668961
- Cited by
- 315
- References
- 9
- FWCI
- 14.35
- Type
- journal article
- Language
- en
- Open access
- green
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- Kleppe, M., Kwak, M., Koppikar, P., Riester, M., Keller, M., Bastian, L., Hricik, T., Bhagwat, N., McKenney, A. S., Papalexi, E., Abdel-Wahab, O., Rampal, R., Marubayashi, S., Chen, J. J., Romanet, V., Fridman, J. S., Bromberg, J., Teruya-Feldstein, J., Murakami, M., . . . Levine, R. L. (2015). JAK–STAT Pathway Activation in Malignant and Nonmalignant Cells Contributes to MPN Pathogenesis and Therapeutic Response. Cancer Discovery. https://doi.org/10.1158/2159-8290.cd-14-0736
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