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 Scopus citations

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 - Jan 1 2016

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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