Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocytic leukemia cells correlates with survival capacity

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

“…Bcl-xL is not highly expressed in CLL cells in the blood, but is significantly expressed at higher levels in the lymph nodes. 24 In addition, our current observations using IL4/CD40L to mimic this microenvironment suggest that SSA alone may be less effective at treating CLL cells in the lymph node niche. These data are supported by results with Raji cells, which retained Bcl-xL expression and were relatively insensitive to SSA-induced apoptosis, although Mcl-1 was spliced and down-regulated.…”

“…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.…”

“…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. [26][27][28][29] Several pan-Bcl-2 family inhibitors such as obatoclax, sabutoclax and AT-101 have been developed with low micromolar potency against Mcl-1.…”

CD40 stimulation sensitizes CLL cells to rituximab-induced cell death

“…As CD40 stimulation is considered to be part of the micro-environmental stimuli rendering CLL cells less sensitive to cytostatic drugs, our data provide a strong rationale for adding rituximab to * * ** * CD40 stimulation sensitizes CLL cells to rituximab-induced cell death M Jak et al chemotherapy regimens, like, for example, fludarabine and cyclophosphamide. By bypassing the anti-apoptotic machinery, 6,7,17 RXL is able to induce caspase-independent cell death in CD40-stimulated CLL cells that are resistant to various drugs as result of upregulation of Bcl-2 family members. 5,6 Moreover, our findings suggest that it might be very relevant to combine rituximab with other ROS-inducing drugs like arsenic trioxide 56 or cisplatin.…”

“…2,4 We have previously shown that in vitro CD40 stimulation of peripheral bloodderived CLL cells can to a certain extent mimic the lymph node micro-environment and result in resistance to cytotoxic drugs. [5][6][7] Recently, it has been shown in a large randomized phase III trial that addition of the chimeric anti-CD20 monoclonal antibody (mAb) rituximab (R) to fludarabine and cyclophosphamide improves both progression free survival and overall survival in p53 functional, previously untreated CLL patients. 8 This is remarkable in view of the relatively low efficacy of rituximab when used as monotherapy at dosages used in the treatment of lymphoma.…”