Figure 7.

H3K27Ac ChIP-seq of AML patient samples stratified by FAB subtype identifies enrichment of AHR signaling components and hematopoietic TFs in monocytic leukemias. A and B, Analysis of H3K27Ac ChIP-Seq AML samples (41) with known FAB designations (n = 8 M0–M2 FAB, 17 M4–M5). A, PCA. B, Volcano plots representing the 6,076 differentially H3K27-acetylated genes between the undifferentiated M0 to M2 FAB subtype and M4 and M5 FAB monocytic subtype. Each point represents a single gene enrichment versus –log₁₀ P value. C, Relative expression levels (reads per kilobase per million mapped, RPKM) of canonical AHR genes across FAB groups within the Beat AML patient RNA-sequencing data set (all samples with both RNA-sequencing data and FAB subtype data, 29 M0–M2 samples and 34 M4–M5 samples). D, Cartoon schematic detailing findings and hypothesis. In brief, we hypothesize that BETi sensitivity and resistance are governed by leukemic differentiation state. Monocytic AMLs have higher expression of TFs (SPI1, FOS, JUNB, etc.) and increased AHR signaling, which recruit histone acetylation machinery to acetylate histone residues that BRD4 binds to mediate downstream affects. Thus, monocytic AMLs have more targetable sites for BETi and increased sensitivity. Conversely, BCL2i/CDK4/6i are more efficacious in undifferentiated leukemias, which characteristically have higher expression of these genes, and the combination with BETi may help overcome drug resistance development as a consequence of altered maturation state. Left, decreased BRD4 dependency due to decreased recruitment of histone-modifying machinery and AHR signaling. Right, increased BRD4 dependency due to increased histone acetylation driven by hematopoietic TFs and AHR recruitment.