Interplay between intrinsic and extrinsic resistance mechanisms in monocytic AML. Idasanutlin (IDA) and venetoclax (VEN) treatment enhances CEBPB-mediated intrinsic and IL-1- and TNF-α-mediated extrinsic drug resistance in monocytic AML. CEBPB leads to an increased expression of BCL2A1, MCL-1, IL-1–TNF–NF-κB pathway genes and monocytic differentiation, whereas expression of BCL-2, CASP3, and CASP6 decreased. Abnormal monocytes in M4/M5 leukemia secrete IL-1 and TNF-α, which in turn confers extrinsic drug resistance to M4/M5 blasts expressing high levels of IL-1 and TNF-α receptors. Through an autocrine activation loop, IL-1β induces its own expression and expression of other prosurvival cytokines. IL-1 and TNF-α induce an increase in CEBPB in M4/M5 AML. Figure created with Biorender.com.

Interplay between intrinsic and extrinsic resistance mechanisms in monocytic AML. Idasanutlin (IDA) and venetoclax (VEN) treatment enhances CEBPB-mediated intrinsic and IL-1- and TNF-α-mediated extrinsic drug resistance in monocytic AML. CEBPB leads to an increased expression of BCL2A1, MCL-1, IL-1–TNF–NF-κB pathway genes and monocytic differentiation, whereas expression of BCL-2, CASP3, and CASP6 decreased. Abnormal monocytes in M4/M5 leukemia secrete IL-1 and TNF-α, which in turn confers extrinsic drug resistance to M4/M5 blasts expressing high levels of IL-1 and TNF-α receptors. Through an autocrine activation loop, IL-1β induces its own expression and expression of other prosurvival cytokines. IL-1 and TNF-α induce an increase in CEBPB in M4/M5 AML. Figure created with Biorender.com.

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