title: 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.
authors.affiliation: Australian Cancer Research Foundation Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia;
authors.forename: James Q
authors.identifier: 0000-0001-8534-255X
authors.initials: JQ
authors.lastname: Wang
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX; and.
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
authors.forename: Christopher C
authors.identifier: 0000-0001-5296-6155
authors.initials: CC
authors.lastname: Goodnow
authors.affiliation: Australian Cancer Research Foundation Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia;
authors.forename: Keisuke
authors.identifier: 0000-0002-7381-9450
authors.initials: K
authors.lastname: Horikawa
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D010950:Plasma Cells / Q000276:immunology*; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D026901:Membrane Transport Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; C512254:UNC93B1 protein, mouse