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Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome.

Publication ,  Journal Article
Kam, AYF; Piryani, SO; McCall, CM; Park, HS; Rizzieri, DA; Doan, PL
Published in: Clin Cancer Res
July 1, 2019

PURPOSE: Myelodysplastic syndrome (MDS) is associated with a dysregulated innate immune system. The purpose of this study was to determine whether modulation of the innate immune system via high mobility group box-1 (HMGB1) could reduce cell viability in MDS. EXPERIMENTAL DESIGN: We quantified HMGB1 in an MDS cell line MDS-L and in primary MDS cells compared with nonmalignant hematopoietic cells. We performed loss-of-function studies of HMGB1 using pooled siRNAs and a small-molecule inhibitor sivelestat compared with standard chemotherapy. We measured levels of engraftment of MDS-L cells in NOD-scidIL2Rgnull (NSG) mice following treatment with sivelestat. Mechanistically, we interrogated cell survival pathways and 45 targets within the NFκB pathway using both protein analysis and a proteome profiler array. RESULTS: We discovered that HMGB1 had increased expression in both MDS-L cells and in primary CD34+ MDS cells compared with healthy CD34+ hematopoietic cells. Sivelestat impaired MDS cell expansion, increased cellular death, and spared healthy hematopoietic cells. MDS-L marrow engraftment is reduced significantly at 17 weeks following treatment with sivelestat compared with control mice. Treatment of CD34+ MDS cells with sivelestat and azacitidine or decitabine was additive to increase apoptotic cell death compared with chemotherapy alone. Sivelestat promoted apoptosis with increased expression of PUMA, activated caspase 3, and increased DNA double-strand breaks. Inhibition of HMGB1 reduced levels of Toll-like receptors (TLR) and suppressed activation of NFκB in MDS-L cells. CONCLUSIONS: Inhibition of HMGB1 could promote MDS cell death and alter innate immune responses via suppression of NFκB pathways.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

July 1, 2019

Volume

25

Issue

13

Start / End Page

4155 / 4167

Location

United States

Related Subject Headings

  • Toll-Like Receptors
  • Oncology & Carcinogenesis
  • NF-kappa B
  • Myelodysplastic Syndromes
  • Mutation
  • Mice, Knockout
  • Mice
  • Immunophenotyping
  • Immunohistochemistry
  • Immunity, Innate
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Kam, A. Y. F., Piryani, S. O., McCall, C. M., Park, H. S., Rizzieri, D. A., & Doan, P. L. (2019). Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome. Clin Cancer Res, 25(13), 4155–4167. https://doi.org/10.1158/1078-0432.CCR-18-3517
Kam, Angel Y. F., Sadhna O. Piryani, Chad M. McCall, Hee Su Park, David A. Rizzieri, and Phuong L. Doan. “Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome.Clin Cancer Res 25, no. 13 (July 1, 2019): 4155–67. https://doi.org/10.1158/1078-0432.CCR-18-3517.
Kam AYF, Piryani SO, McCall CM, Park HS, Rizzieri DA, Doan PL. Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome. Clin Cancer Res. 2019 Jul 1;25(13):4155–67.
Kam, Angel Y. F., et al. “Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome.Clin Cancer Res, vol. 25, no. 13, July 2019, pp. 4155–67. Pubmed, doi:10.1158/1078-0432.CCR-18-3517.
Kam AYF, Piryani SO, McCall CM, Park HS, Rizzieri DA, Doan PL. Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome. Clin Cancer Res. 2019 Jul 1;25(13):4155–4167.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

July 1, 2019

Volume

25

Issue

13

Start / End Page

4155 / 4167

Location

United States

Related Subject Headings

  • Toll-Like Receptors
  • Oncology & Carcinogenesis
  • NF-kappa B
  • Myelodysplastic Syndromes
  • Mutation
  • Mice, Knockout
  • Mice
  • Immunophenotyping
  • Immunohistochemistry
  • Immunity, Innate