CML: the good, the better, and the difficult choices.

It is unclear if this is a direct effect or mediated by kinase inhibition. Sphingolipids are also known as mediators of mitochondrial apopto-sis. Consistent with the antiapoptotic effect of glucosylceramide, BCR stimulation reduced the effect of the mitochondria-targeting drug ABT-737. Concomitant treatment with low doses of the kinase (and apparently UGCG) inhibitors GS-1101 and ibrutinib restored the activity of ABT-737 leading to CLL cell death. Thus, the 2 drugs may also be regarded as sensitizers for ABT-737, opening up the possibility for novel drug combinations. The discovery adds novel aspects to our understanding of BCR function as well as the potential implications for drug therapy. It will help to explain changes in (sphingo-) lipid metabolism as well as BCR-triggered gene regulation in CLL. This opens up a whole new approach for treatment options, the mechanism of action and functional downstream effects of novel kinase inhibitors as well as many other drugs that act on the BCR or one of its signaling pathway components. CLL therapy continues to be a success story. Conflict-of-interest disclosure: The author declares no competing financial interests. ■ REFERENCES 1. Schwamb J, Feldhaus V, Baumann M, et al. B-cell receptor triggers drug sensitivity of primary CLL cells by controlling glycosylation of ceramides. et al. Whole-genome sequencing identifies recurrent mutations in chronic lym-phocytic leukaemia. The B-cell receptor signaling pathway as atherapeutic target. D et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. 7. Steininger C, Widhopf GF 2nd, Ghia EM, et al. Re-combinant antibodies encoded by IGHV1-69 react with pUL32, a phosphoprotein of cytomegalovirus and B-cell superantigen. isoform-seleective inhibitor of phosphatidylinositol 3-kinase P110, demonstrates clinical activity and pharmaco-dynamic effects in patients with relapsed or refractory chronic lymphocytic leukemia [abstract]. et al. The BrutonЈs tyrosine kinase (BTK) inhibitor PCI-32765 induces durable responses in relapsed or refractory (R/R) chronic lympho-cytic leukemia/small lymphocytic lymphoma (CLL/SLL): Follow-up of a phase Ib/II study [abstract].pression of fat and muscle genes in B-cell chronic lympho-cytic leukemia with high lipoprotein lipase expression. In this issue of Blood, Radich and colleagues from 4 cooperative groups report on the results of a randomized study of dasatinib versus imatinib as initial treatment for patients with chronic phase chronic myeloid leukemia (CML). 1 T his study is the sequel to a trial where they first compared imatinib standard-dose to imatinib high-dose. The results of the second portion of the study …