BET Bromodomain Inhibition Reduces Leukemic Burden and Prolongs Survival In The Eμ-TCL1 Transgenic Mouse Model Of Chronic Lymphocytic Leukemia (CLL) Independent Of TP53 Mutation Status
Larsson CA, Kojima K, Wang Y et al.
Key Points:
Elevated MYC expression correlates with B-CLL progression & MYC repression can be achieved by Jq1, a BET bromodomain inhibitor.
In vitro treatment with Jq1 showed significant reduction in proliferation of human B-CLL cell lines, Mec-1, Mec-2, and WaC3 (IC50 values: 1.12, 0.68, and 0.64 μM, respectively).
Intraperitoneal Jq1 treatment to Eμ-TCL1 (n=13) & Eμ-TCL1:p53R172H/+ (n=9) mice revealed decrease in peripheral blood lymphocytes and prolonged survival compared to mice recieving placebo.
Fludarabine resistance and TP53 deletion did not affect sensitivity of leukemic cell to Jq1; however preliminary gene analysis suggests effect of Jq1 might not be MYC dependent.
Implications:
- BET bromodomain inhibition significantly decreases B-CLL proliferation in-vivo and in xenograft mouse model, however mechanism seems to be MYC independent.
View the original abstract on the ASH website.
