The mechanism of GSI resistance in T cell acute lymphoblastic leukemia


γ-secretase inhibitor (GSIs) has been well-proved to suppress the activation of NOTCH1 mutations, which is a critical oncogene in T cell acute lymphoblastic leukemia (T-ALL). However, the effect remains to be modest and transient in clinical trials and mouse models, due to the durg resistance. Knoechel et al. identified BRD4 is an important regulator of GSI resistance in T-ALL cells, and the combination of GSI and JQ1, the BRD4 inhibitor, is effective against T-ALL in vivo. The letter was published on Nature Genetics.


Researchers established a model of T-ALL resistance, and found GSI-tolerance 'persister' cells are already present in the absence of NOTCH1 signaling. By using a lentiviral short hairpin RNA (shRNA) knockdown screen, they identified BRD4 shRNAs are enable to reduce the proliferation of persister cells specifically, indicating BRD4 is associated with GSI resistance. Mechanismly, BRD4 binds to the enhancers of key T-ALL genes, such as MYC and BCL2, to promote the expression of factors related to NOTCH1 activation. The BRD4 inhibitor JQ1 reduces the expression of these factors and consequently leads to growth arrest and apoptosis of persister cells, without affecting GSI-sensitive cells. The combination treatment of GSI and JQ1 was proved to be more effective in suppressing tumor cell growth and survival both in vitro and in vivo, and suggested a novel combination therapy of T-ALL.


Nat Genet. 2014 Apr;46(4):364-70.

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