Inhibiting TLR9 and other UNC93B1-dependent TLRs paradoxically increases accumulation of MYD88L265P plasmablasts in vivo

James Q. Wang, Bruce Beutler, Christopher C. Goodnow, Keisuke Horikawa

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The MYD88L265P mutation is found in 2% to 10% of chronic lymphocytic leukemia, 29% of activated B-cell type diffuse large B-cell lymphoma and 90% of Waldenström macroglobulinemia, making it conceptually attractive to treat these malignancies with inhibitors of endosomal Toll-like receptors (TLR9, TLR7) that activate MYD88. Here we show that genetic inhibition of endosomal TLRs has the opposite effect on accumulation of MYD88L265P B cells in vitro and in vivo. Activated mature B cells from wild-type, Unc93b13d/3d-mutant, or Tlr9-deficient mice were transduced with retrovirus encoding MYD88L265P and analyzed either in vitro or after transplantation into Rag1-/- recipient mice. Unc93b13d/3d mutation, which blocks TLR9 and TLR7 signaling, or Tlr9 deficiency suppressed MYD88L265P B-cell growth in vitro but paradoxically increased in vivo accumulation of MYD88L265P B cells as CD19low plasmablasts by 10- to 100-fold. These results reveal an unexpected, powerful inhibitory effect of TLR9 on MYD88L265P B-cell proliferation and differentiation that appears independent of TLR7, and they providea preclinical indicator for caution in clinical trials of TLR7/9 inhibitors for MYD88L265P B-cell malignancies.

Original languageEnglish (US)
Pages (from-to)1604-1608
Number of pages5
JournalBlood
Volume128
Issue number12
DOIs
StatePublished - 2016

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B-Lymphocytes
Cells
Toll-Like Receptors
Waldenstrom Macroglobulinemia
Cell proliferation
Cell growth
Mutation
Lymphoma, Large B-Cell, Diffuse
B-Cell Chronic Lymphocytic Leukemia
Retroviridae
Cell Differentiation
Neoplasms
Transplantation
Cell Proliferation
Clinical Trials
Growth
In Vitro Techniques

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Inhibiting TLR9 and other UNC93B1-dependent TLRs paradoxically increases accumulation of MYD88L265P plasmablasts in vivo. / Wang, James Q.; Beutler, Bruce; Goodnow, Christopher C.; Horikawa, Keisuke.

In: Blood, Vol. 128, No. 12, 2016, p. 1604-1608.

Research output: Contribution to journalArticle

Wang, James Q. ; Beutler, Bruce ; Goodnow, Christopher C. ; Horikawa, Keisuke. / Inhibiting TLR9 and other UNC93B1-dependent TLRs paradoxically increases accumulation of MYD88L265P plasmablasts in vivo. In: Blood. 2016 ; Vol. 128, No. 12. pp. 1604-1608.
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