Figure 6.
miR-29 is upregulated and TRAF4 repressed during therapy with BCR inhibitors. (A) Normalized MYC expression in 16 CLL patients before (Pre Ibr) and during ibrutinib (Post Ibr) therapy (weeks 2-12 on therapy depending on the sample availability; for patient characteristics, see supplemental Table 2; CLL 44-46, 48-51, 54, 56-63). (B-C) Normalized expression of miR-29a/b/c in 15 CLL patients (B) or TRAF4 mRNA (C) in 16 CLL patients before (Pre Ibr) and during ibrutinib (Post Ibr) therapy (weeks 2-12 on therapy depending on sample availability, for patient characteristics, see supplemental Table 2; CLL 45-51, 54, 55, 57-60, 62-63 for panel B; CLL 44-46, 48-51, 54, 56-63 for panel C). (Di) Representative immunoblot of TRAF4 protein levels in 2 CLL patients before (Pre Ibr) and during ibrutinib therapy (CLL 48 and 50). (Dii) Densitometric quantification of TRAF4 protein levels analyzed by immunoblotting in all available CLL patients before (Pre Ibr) and during ibrutinib (Post Ibr) therapy (n = 13; weeks 2-12, n = 12; week 1, n = 1; for patient characteristics, see supplemental Table 2; CLL 44-53, 61-63). (E-F) Normalized expression of miR-29a/b/c (E) and TRAF4 (F) in 8 CLL patients before (Pre Idela) and during single agent idelalisib (Post Idela) therapy (weeks 5-6 of therapy depending on sample availability; for patient characteristics, see supplemental Table 2; CLL 64-71). The statistical differences for A to F were tested by Wilcoxon matched pairs test. (Gi) Representative immunoblot of pIKKα/β expression after stimulation with CD40L (1 µg/mL; 3 minutes) in 2 CLL patients before (Ibr −) and during ibrutinib (Ibr +) therapy in vivo (CLL 50 and 63). (Gii) Densitometric quantification of pIKKα/β levels for replicates of the experiment described in panel Gi (n = 5; week 4, n = 2; week 6, n = 1; week 12, n = 1; week 15, n = 1). CLL patients before (Pre) and during ibrutinib (Post Ibr) were analyzed (for patient characteristics, see supplemental Table 2; CLL 47, 50, 61-63). P value was tested by paired t test, and the error bars indicate SEM.

miR-29 is upregulated and TRAF4 repressed during therapy with BCR inhibitors. (A) Normalized MYC expression in 16 CLL patients before (Pre Ibr) and during ibrutinib (Post Ibr) therapy (weeks 2-12 on therapy depending on the sample availability; for patient characteristics, see supplemental Table 2; CLL 44-46, 48-51, 54, 56-63). (B-C) Normalized expression of miR-29a/b/c in 15 CLL patients (B) or TRAF4 mRNA (C) in 16 CLL patients before (Pre Ibr) and during ibrutinib (Post Ibr) therapy (weeks 2-12 on therapy depending on sample availability, for patient characteristics, see supplemental Table 2; CLL 45-51, 54, 55, 57-60, 62-63 for panel B; CLL 44-46, 48-51, 54, 56-63 for panel C). (Di) Representative immunoblot of TRAF4 protein levels in 2 CLL patients before (Pre Ibr) and during ibrutinib therapy (CLL 48 and 50). (Dii) Densitometric quantification of TRAF4 protein levels analyzed by immunoblotting in all available CLL patients before (Pre Ibr) and during ibrutinib (Post Ibr) therapy (n = 13; weeks 2-12, n = 12; week 1, n = 1; for patient characteristics, see supplemental Table 2; CLL 44-53, 61-63). (E-F) Normalized expression of miR-29a/b/c (E) and TRAF4 (F) in 8 CLL patients before (Pre Idela) and during single agent idelalisib (Post Idela) therapy (weeks 5-6 of therapy depending on sample availability; for patient characteristics, see supplemental Table 2; CLL 64-71). The statistical differences for A to F were tested by Wilcoxon matched pairs test. (Gi) Representative immunoblot of pIKKα/β expression after stimulation with CD40L (1 µg/mL; 3 minutes) in 2 CLL patients before (Ibr −) and during ibrutinib (Ibr +) therapy in vivo (CLL 50 and 63). (Gii) Densitometric quantification of pIKKα/β levels for replicates of the experiment described in panel Gi (n = 5; week 4, n = 2; week 6, n = 1; week 12, n = 1; week 15, n = 1). CLL patients before (Pre) and during ibrutinib (Post Ibr) were analyzed (for patient characteristics, see supplemental Table 2; CLL 47, 50, 61-63). P value was tested by paired t test, and the error bars indicate SEM.

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