p300 regulates multiple downstream mediators of BETi resistance. (A) Average binding curve profiles for p300 in the indicated isogenic SKNO1 with different degrees of BETi resistance, centered at/around regulatory regions of the rescued (left) and evolution (right) genes. (B-D) Examples of binding kinetics of p300 at ETV6 (a rescued gene) (B), CCR7 (an evolution gene) (C), and NCAM1 (an evolution gene) (D) in BETi-sensitive and BETi-resistant settings. (E) Continued from Figure 5B, experimental approach to the assessment of transcriptional changes during the longitudinal scale of establishment of resistance to BETi and sensitivity toward p300i. (F) Longitudinal analysis of expression of SKNO1 evolution genes that code for ligands and signaling receptors, during all stages of resistance to BETi, with or without addition of p300i for 24 hours. Individual genes within the group were chosen based on their structural assignment per gene ontology analysis. Shown are average FPKM values from 3 biological replicates and SD. (G) Assessment of cellular viability after NCAM1 knockdown in the indicated SKNO1 isogenic cells for 120 hours. Shown are percentages normalized to Luc controls and SD from 3 biological replicates. (H) Longitudinal analysis of expression of all OCI-AML3-related “inflammation” genes, during all stages of resistance to BETi, with or without addition of p300i for 24 hours. Shown are average FPKM values from 3 biological replicates and SD. (I) Assessment of cellular viability after S100A9 knockdown in the indicated isogenic cells for 120 hours. Shown are the percentages normalized to Luc controls and SD from 3 biological replicates. (J) Analysis of cellular viability after treatment with either DMSO or paquinimod in the indicated OCI-AML3 isogenic cells for 72 hours. Shown are percentages normalized to DMSO-treated controls and SD from 3 biological replicates. (K) Longitudinal analysis of expression of all OCI-AML3–related “interferon” genes, during all stages of resistance to BETi, with or without addition of p300i for 24 hours. Shown are average FPKM values from 3 biological replicates and SD. (L) Analysis of cellular viability after STAT1 knockdown and DMSO or p300i treatment for 120 hours in the indicated isogenic cell lines. Shown are percentages normalized to DMSO and SD from 3 biological replicates. Chr, chromosome; ETV6, ETS variant transcription factor 6; FPKM, fragments per kilobase per million mapped fragments; RPM, reads per million.
Figure 6.

p300 regulates multiple downstream mediators of BETi resistance. (A) Average binding curve profiles for p300 in the indicated isogenic SKNO1 with different degrees of BETi resistance, centered at/around regulatory regions of the rescued (left) and evolution (right) genes. (B-D) Examples of binding kinetics of p300 at ETV6 (a rescued gene) (B), CCR7 (an evolution gene) (C), and NCAM1 (an evolution gene) (D) in BETi-sensitive and BETi-resistant settings. (E) Continued from Figure 5B, experimental approach to the assessment of transcriptional changes during the longitudinal scale of establishment of resistance to BETi and sensitivity toward p300i. (F) Longitudinal analysis of expression of SKNO1 evolution genes that code for ligands and signaling receptors, during all stages of resistance to BETi, with or without addition of p300i for 24 hours. Individual genes within the group were chosen based on their structural assignment per gene ontology analysis. Shown are average FPKM values from 3 biological replicates and SD. (G) Assessment of cellular viability after NCAM1 knockdown in the indicated SKNO1 isogenic cells for 120 hours. Shown are percentages normalized to Luc controls and SD from 3 biological replicates. (H) Longitudinal analysis of expression of all OCI-AML3-related “inflammation” genes, during all stages of resistance to BETi, with or without addition of p300i for 24 hours. Shown are average FPKM values from 3 biological replicates and SD. (I) Assessment of cellular viability after S100A9 knockdown in the indicated isogenic cells for 120 hours. Shown are the percentages normalized to Luc controls and SD from 3 biological replicates. (J) Analysis of cellular viability after treatment with either DMSO or paquinimod in the indicated OCI-AML3 isogenic cells for 72 hours. Shown are percentages normalized to DMSO-treated controls and SD from 3 biological replicates. (K) Longitudinal analysis of expression of all OCI-AML3–related “interferon” genes, during all stages of resistance to BETi, with or without addition of p300i for 24 hours. Shown are average FPKM values from 3 biological replicates and SD. (L) Analysis of cellular viability after STAT1 knockdown and DMSO or p300i treatment for 120 hours in the indicated isogenic cell lines. Shown are percentages normalized to DMSO and SD from 3 biological replicates. Chr, chromosome; ETV6, ETS variant transcription factor 6; FPKM, fragments per kilobase per million mapped fragments; RPM, reads per million.

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