Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative disorder of B lymphocytes. It has an extremely variable clinical course. Some patients have a rather indolent course, whereas others are known to have a rapidly progressive disease. Most patients die from causes related to CLL that can be due to bone marrow failure, infection, or transformation to a high-grade lymphoma. Clinical stratification of CLL has revealed that a subset of patients with poor prognosis harbor cytogenetic alterations and lack mutations at the immunoglobulin locus. Therefore, the development of additional molecular biomarkers for patients at high risk for early lethality from CLL could help direct their care toward enrollment in clinical trials of promising experimental approaches such as inhibitors of BCL2 or BCR signaling or CD19 chimeric antigen receptor T cells (which have been shown to eradicate CLL in patients who have failed other approaches). In this issue, Mansouri et al. report that somatic mutations in the NFKBIE gene occur in 7% of poor prognosis patients, and this may be a common mechanism contributing to disease progression by sustaining the survival of malignant CLL cells.

The NF-κB pathway is ubiquitously activated in CLL cells by cell surface receptor signaling cascades through the B cell receptor and Toll-like receptors, so this identification of additional mutational events that reinforce NF-κB signaling appeared biochemically redundant. NFKBIE encodes the IkBε protein, a potent and seemingly stoichiometric inhibitor of the IkB kinase (IKK) in CLL cells as demonstrated by Mansouri et al. Surprisingly, even partial depletion of NFKBIE with RNA interference in cell culture was sufficient to activate IKK and promote NF-κB transcriptional activation, consistent with the findings that the NFKBIE mutations are heterozygous in CLL samples and that these samples had modest increases in NF-κB signaling. Whether the most recurrent NFKBIE mutation identified in this work (a 4-bp deletion in exon 1 that resulted in a frame shift and potentially expressed truncated protein) has neomorphic oncogenic functions besides the inability to inhibit IKK remains unknown.

More broadly, the finding of heterozygous NFKBIE mutations as a marker of poor prognosis raises the possibility that similar mutations or heterozygous loss of NFKBIE caused by genetic deletion or epigenetic silencing may also further sculpt NF-κB signaling and thereby promote the progression of more common malignancies. Unfortunately, most of the publicly available tumor genomes include a significant amount of contaminating normal cells, and therefore haploid loss of NFKBIE may not be appreciated. Single nuclei sequencing of neoplastic cells isolated freshly from tumors will address this and other issues of potential haploidy in cancer by unambiguously determining the cancer genome and concurrent genetic events. For CLL patients, the finding of the NFKBIE mutations in high-risk patients refocuses our attention on developing NF-κB inhibitors to use in tandem with other approaches and for considering experimental clinical trials for such patients.

, et al
J. Exp. Med.