TY - JOUR
T1 - Inhibiting TLR9 and other UNC93B1-dependent TLRs paradoxically increases accumulation of MYD88L265P plasmablasts in vivo
AU - Wang, James Q.
AU - Beutler, Bruce
AU - Goodnow, Christopher C.
AU - Horikawa, Keisuke
N1 - Funding Information:
The authors thank Paula Gonzalez for advice on ELISA and the Australian Phenomics Facility for expert care and genotyping of animals. This work was supported by grants from the National Institutes of Health, National Institute of Allergy and Infectious Diseases (AI100627) (C.C.G., B.B.) and the National Health and Medical Research Council (1016953, 585490, and 1081858 [C.C.G.]; 1086770 [K.H.]). J.Q.W is a candidate at the Australian National University and is supported by an Australian Postgraduate Award.
Publisher Copyright:
© 2016 by The American Society of Hematology.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85015685500&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85015685500&partnerID=8YFLogxK
U2 - 10.1182/blood-2016-03-708065
DO - 10.1182/blood-2016-03-708065
M3 - Article
C2 - 27458005
AN - SCOPUS:85015685500
VL - 128
SP - 1604
EP - 1608
JO - Blood
JF - Blood
SN - 0006-4971
IS - 12
ER -