Home Blog of Signal Transduction Epigenetics Epigenetic Reader Domain Interrogating bromodomain inhibitor resistance in KMT2A-rearranged leukemia through combinatorial CRISPR screens

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Interrogating bromodomain inhibitor resistance in KMT2A-rearranged leukemia through combinatorial CRISPR screens

Bromo- and extra-terminal domain inhibitors (BETi) have exhibited therapeutic activities in many cancers. However, the mechanisms controlling BETi response and resistance are not well understood. We conducted genome-wide loss-of-function CRISPR screens using BETi-treated KMT2A-rearranged (KMT2A-r) cell lines. We revealed that Speckle-type POZ protein (SPOP) gene (Speckle Type BTB/POZ Protein) deficiency caused significant BETi resistance, which was further validated in cell lines and xenograft models. Proteomics analysis and a kinase-vulnerability CRISPR screen indicated that cells treated with BETi are sensitive to GSK3 perturbation. Pharmaceutical inhibition of GSK3 reversed the BETi-resistance phenotype. Based on this observation, a combination therapy regimen inhibiting both BET and GSK3 was developed to impede KMT2A-r leukemia progression in patient-derived xenografts in vivo. Our results revealed molecular mechanisms underlying BETi resistance and a promising combination treatment regimen of ABBV-744 and CHIR-98014 by utilizing unique ex vivo and in vivo KMT2A-r PDX models.

 

Comments:

Your study focused on investigating the mechanisms controlling response and resistance to Bromo- and Extra-Terminal domain inhibitors (BETi) in KMT2A-rearranged (KMT2A-r) cell lines, which are associated with various cancers. Through genome-wide loss-of-function CRISPR screens, you discovered that the deficiency of the Speckle-type POZ protein (SPOP) gene leads to significant resistance to BETi. This finding was further confirmed in cell lines and xenograft models.

To gain insights into the molecular basis of BETi resistance, you conducted proteomics analysis and a kinase-vulnerability CRISPR screen. The results indicated that cells treated with BETi are sensitive to perturbation of GSK3 (Glycogen Synthase Kinase 3). Furthermore, you demonstrated that pharmaceutical inhibition of GSK3 can reverse the BETi-resistance phenotype.

Building upon these observations, you developed a combination therapy regimen targeting both BET and GSK3 to impede the progression of KMT2A-r leukemia in patient-derived xenografts (PDX) in vivo. The combination treatment involved the use of ABBV-744 (a BET inhibitor) and CHIR-98014 (a GSK3 inhibitor). This approach showed promise in inhibiting KMT2A-r leukemia growth, as demonstrated in the unique ex vivo and in vivo KMT2A-r PDX models used in your study.

Overall, your research provides valuable insights into the molecular mechanisms underlying BETi resistance and highlights a potential therapeutic strategy involving the combination of BET and GSK3 inhibition for KMT2A-r cancers.

Related Products

Cat.No. Product Name Information
S8723 ABBV-744 ABBV-744 is a BDII-selective BET bromodomain inhibitor that inhibits BRD2, BRD3 and BRD4. It is developed for treating AML and cancers.

Related Targets

Epigenetic Reader Domain