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

ABSTRACT: The MYD88(L265P) 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 MYD88(L265P) B cells in vitro and in vivo. Activated mature B cells from wild-type, Unc93b1(3d/3d)-mutant, or Tlr9-deficient mice were transduced with retrovirus encoding MYD88(L265P) and analyzed either in vitro or after transplantation into Rag1(-/-) recipient mice. Unc93b1(3d/3d) mutation, which blocks TLR9 and TLR7 signaling, or Tlr9 deficiency suppressed MYD88(L265P) B-cell growth in vitro but paradoxically increased in vivo accumulation of MYD88(L265P) B cells as CD19(low) plasmablasts by 10- to 100-fold. These results reveal an unexpected, powerful inhibitory effect of TLR9 on MYD88(L265P) B-cell proliferation and differentiation that appears independent of TLR7, and they provide a preclinical indicator for caution in clinical trials of TLR7/9 inhibitors for MYD88(L265P) B-cell malignancies.

SUBMITTER: Wang JQ

PROVIDER: S-EPMC5034740 | biostudies-other | 2016 Sep

REPOSITORIES: biostudies-other

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

Wang James Q JQ Beutler Bruce B Goodnow Christopher C CC Horikawa Keisuke K

Blood 20160725 12

The MYD88(L265P) 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 MYD88(L265P) B cells in vitro and in vivo. Activated mature B cells from wi ...[more]

PMID: 27458005

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Dataset Information

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

Publications

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

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