Cytogenetics in CML: more important than you think.

is a survival-enhancing oncoprotein that is frequently overexpressed in ABC-DLBCL by virtue of gene amplification (focal copy number gains) at 18q. The investigators cleverly recapitulated this aspect of the ABC-DLBCL genetic network by combining the MYD88 allele with a newly developed inducible BCL2 allele in double-transgenic mice that developed tumors resembling human ABC-DLBCL with full penetrance (100% tumor incidence). Knittel et al propose to use these tumors as a heretofore unavailable model system of actionable BCL2 addiction that lends itself to preclinical co-trials of the BCL2 inhibitors venetoclax (ABT-199) and navitoclax (ABT-263) and the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, which synergizes with BCL2 inhibition in killing ABC-DLBCL cells. In summary, Knittel et al produced a mouse model of MYD88-driven ABC-DLBCL that should facilitate efforts to design and test new approaches to treat this difficult-to-cure lymphoma. Thesemay include small-molecule IRAK4 and TAK1 inhibitors currently in the preclinical drug pipeline or combination therapies that target BCL2, MAPK, or JAK-STAT in addition to MYD88-NFkB signaling. Be this as it may, the newly developedMYD88 transgene will also be of value for developing GEMMs for human B-cell tumors (eg, Waldenström macroglobulinemia) for which such models are still lacking. Conflict-of-interest disclosure: The author declares no competing financial interests. n