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 language | English (US) |
|---|---|
| Pages (from-to) | 1604-1608 |
| Number of pages | 5 |
| Journal | Blood |
| Volume | 128 |
| Issue number | 12 |
| DOIs | |
| State | Published - 2016 |
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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 journal › Article
}
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
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 -