Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

“…45,47 It is known that targeting all pro-survival members is critical for efficient apoptosis 48 and CLL is known to have elevated levels of Bcl-2, Bcl-xL and Mcl-1 in lymph nodes. 24 Furthermore, Mcl-1 expression is known to correlate with progressive disease, resistance to chemotherapy and time to first treatment 23 SSA-induced killing of CLL cells was independent of the mutational status of SF3B1 and IGHV, as well as, CD38 and ZAP70 expression. SF3B1 mutations have been shown to be present at sub-clonal levels, 50 however all our SF3B1 mutant samples exhibited deregulated splicing supporting the notion that the SF3B1 mutant protein in these cases has a functional impact.…”

“…22 In CLL, Mcl-1 expression correlates with stage of disease, lymphocyte doubling time, IGHV mutation status, ZAP70 positivity and CD38 expression. 23 Furthermore, the Mcl-1 expression level and Mcl-1:Bax ratio correlate with resistance to fludarabine and time to first treatment. 23 Mcl-1 may also be expressed to a greater extent in CLL lymph nodes compared with blood, where resistance to apoptosis is known to occur.…”

“…23 Furthermore, the Mcl-1 expression level and Mcl-1:Bax ratio correlate with resistance to fludarabine and time to first treatment. 23 Mcl-1 may also be expressed to a greater extent in CLL lymph nodes compared with blood, where resistance to apoptosis is known to occur. 24 The emergence of Bcl-2 inhibitors such as ABT-263 and ABT-199 are showing considerable promise for the treatment of CLL, however these drugs are unable to inhibit the antiapoptotic effects of Mcl-1 conferred by the microenvironment, 25 thus identifying a known mechanism of resistance to these BH3-mimetics.…”

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…101 Resistance to fludarabine may also be mediated by other Bcl-2 family members such as increased expression of Mcl-1, which is associated with a poor prognosis. 102,103 Development of specific Mcl-1 inhibitors is in progress based on the crystal structure of Mcl-1. 104,105 However, Mcl-1 confers less protection against chemotherapy than Bcl-2.…”

N-(4-hydroxyphenyl)retinamide promotes apoptosis of resting and proliferating B-cell chronic lymphocytic leukemia cells and potentiates fludarabine and ABT-737 cytotoxicity

“…6 Especially relevant is Mcl-1, for which elevated levels are associated with poor treatment response and high risk of CLL disease progression. 7,8 Mcl-1 reduction strategies were able to restore in vitro chemotherapic cytotoxicity. 6,9 CLL cells are sensitive to oxidative stress.…”