Figure 1.
TLR2 expression and activation extends survival of AML-bearing mice. (A) Box plots of log2 RNA expression of TLR1-TLR10 in patients with AML (n = 483). (B) Box plots of log2 RNA expression of TLR1-TLR10 in patients with AML with DNMT3A, FLT3, or coincident DNMT3A/FLT3, or other mutations (n = 483). (C) Heat map of Tlr1-Tlr13 expression in cKit+ cells isolated from moribund Dnmt3a+/−Flt3ITD AML mice (n = 3) and age-matched Flt3ITD MPN (n = 3). WT mouse LSK, CMP, and GMP are shown as a normal baseline comparison. (D) Transplantation and treatment schematic for panels E-G. CD45.2+Dnmt3a+/−Flt3ITD AML cells transplanted into CD45.1+ WT recipient mice. Treatment was initiated 14 days after transplant. PB collection time points indicated “t” in days after treatment with indicated TLR agonists. (E) Average ± SEM percent CD45.2+Dnmt3a+/−Flt3ITD AML cells in PB from transplanted mice. Day 0 time point was immediately before treatment, then sampling at days 1, 7, and 15 after treatment with PBS, Pam3CSK4, Pam2CSK4, Poly(I:C), Poly(A:U), LPS, or R848 (n = 3/group). Arrow indicates agonist treatment. (F) Average ± SEM percent CD11b+ cells in CD45.2+Dnmt3a+/−Flt3ITD PB cells from transplanted mice. Day 0 time point was immediately before treatment, then sampling at days 1, 7, and 15 after treatment with PBS, Pam3CSK4, Pam2CSK4, Poly(I:C), Poly(A:U), LPS, or R848 (n = 3/group). Arrow indicates agonist treatment. (G) Kaplan-Meier survival curves of Dnmt3a+/−Flt3ITD AML-transplanted mice (n = 15/group) and treated with Pam3CSK4 or PBS control. Arrow indicates treatment on day 14 after transplant. (H) Kaplan-Meier survival curves of Dnmt3a+/−Flt3ITD AML-transplanted mice (n = 15/group) and treated with Pam2CSK4 or PBS control. Arrow indicates treatment on day 14 after transplant. (I) Kaplan-Meier survival curves of murine MLL-AF9 AML-transplanted WT recipients treated with 1 dose of Pam3CSK4 or PBS control. Arrow indicates time of treatment (n = 5/group). (J) Kaplan-Meier survival curves of human OCI-AML3 AML cells transplanted into NSG recipient mice treated with PBS (n = 16) or Pam3CSK4 (n = 15). Arrow indicates treatment on day 10 after transplant. Statistical significance by unpaired t test (E-F) or Kaplan-Meier log rank test (G-J). ∗∗∗∗P < .0001, ∗∗∗P < .001, ∗∗P < .01, ∗P < .05. SEM, standard error of the mean.

TLR2 expression and activation extends survival of AML-bearing mice. (A) Box plots of log2 RNA expression of TLR1-TLR10 in patients with AML (n = 483). (B) Box plots of log2 RNA expression of TLR1-TLR10 in patients with AML with DNMT3A, FLT3, or coincident DNMT3A/FLT3, or other mutations (n = 483). (C) Heat map of Tlr1-Tlr13 expression in cKit+ cells isolated from moribund Dnmt3a+/−Flt3ITD AML mice (n = 3) and age-matched Flt3ITD MPN (n = 3). WT mouse LSK, CMP, and GMP are shown as a normal baseline comparison. (D) Transplantation and treatment schematic for panels E-G. CD45.2+Dnmt3a+/−Flt3ITD AML cells transplanted into CD45.1+ WT recipient mice. Treatment was initiated 14 days after transplant. PB collection time points indicated “t” in days after treatment with indicated TLR agonists. (E) Average ± SEM percent CD45.2+Dnmt3a+/−Flt3ITD AML cells in PB from transplanted mice. Day 0 time point was immediately before treatment, then sampling at days 1, 7, and 15 after treatment with PBS, Pam3CSK4, Pam2CSK4, Poly(I:C), Poly(A:U), LPS, or R848 (n = 3/group). Arrow indicates agonist treatment. (F) Average ± SEM percent CD11b+ cells in CD45.2+Dnmt3a+/−Flt3ITD PB cells from transplanted mice. Day 0 time point was immediately before treatment, then sampling at days 1, 7, and 15 after treatment with PBS, Pam3CSK4, Pam2CSK4, Poly(I:C), Poly(A:U), LPS, or R848 (n = 3/group). Arrow indicates agonist treatment. (G) Kaplan-Meier survival curves of Dnmt3a+/−Flt3ITD AML-transplanted mice (n = 15/group) and treated with Pam3CSK4 or PBS control. Arrow indicates treatment on day 14 after transplant. (H) Kaplan-Meier survival curves of Dnmt3a+/−Flt3ITD AML-transplanted mice (n = 15/group) and treated with Pam2CSK4 or PBS control. Arrow indicates treatment on day 14 after transplant. (I) Kaplan-Meier survival curves of murine MLL-AF9 AML-transplanted WT recipients treated with 1 dose of Pam3CSK4 or PBS control. Arrow indicates time of treatment (n = 5/group). (J) Kaplan-Meier survival curves of human OCI-AML3 AML cells transplanted into NSG recipient mice treated with PBS (n = 16) or Pam3CSK4 (n = 15). Arrow indicates treatment on day 10 after transplant. Statistical significance by unpaired t test (E-F) or Kaplan-Meier log rank test (G-J). ∗∗∗∗P < .0001, ∗∗∗P < .001, ∗∗P < .01, ∗P < .05. SEM, standard error of the mean.

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