Subtype assignment of CLL based on B-cell subset associated gene signatures from normal bone marrow - A proof of concept study

作者：Norgaard Caroline Holm^*; Jakobsen Lasse Hjort; Gentles Andrew J; Dybkaer Karen; El Galaly Tarec Christoffer; Bodker Julie Stove; Schmitz Alexander; Johansen Preben; Herold Tobias; Spiekermann Karsten; Brown Jennifer R; Klitgaard Josephine L; Johnsen Hans Erik; Bogsted Martin

来源：PLos One, 2018, 13(3): e0193249.

DOI：10.1371/journal.pone.0193249

Diagnostic and prognostic evaluation of chronic lymphocytic leukemia (CLL) involves blood cell counts, immunophenotyping, IgVH mutation status, and cytogenetic analyses. We generated B-cell associated gene-signatures (BAGS) based on six naturally occurring B-cell subsets within normal bone marrow. Our hypothesis is that by segregating CLL according to BAGS, we can identify subtypes with prognostic implications in support of pathogenetic value of BAGS. Microarray-based gene-expression samples from eight independent CLL cohorts (1,024 untreated patients) were BAGS-stratified into pre-BI, pre-BII, immature, naive, memory, or plasma cell subtypes; the majority falling within the memory (24.5- 45.8%) or naive (14.5-32.3%) categories. For a subset of CLL patients (n = 296), time to treatment (TTT) was shorter amongst early differentiation subtypes (pre-BI/pre-BII/immature) compared to late subtypes (memory/plasma cell, HR: 0.53 [0.35-0.78]). Particularly, pre-BII subtype patients had the shortest TTT among all subtypes. Correlates derived for BAGS subtype and IgVH mutation (n = 405) revealed an elevated mutation frequency in late vs. early subtypes (71% vs. 45%, P<.001). Predictions for BAGS subtype resistance towards rituximab and cyclophosphamide varied for rituximab, whereas all subtypes were sensitive to cyclophosphamide. This study supports our hypothesis that BAGS-subtyping may be of tangible prognostic and pathogenetic value for CLL patients.

• 出版日期2018-3-7