TY - JOUR
T1 - Subtype assignment of CLL based on B-cell subset associated gene signatures from normal bone marrow – A proof of concept study
AU - Nørgaard, Caroline Holm
AU - Jakobsen, Lasse Hjort
AU - Gentles, Andrew J.
AU - Dybkær, Karen
AU - El-Galaly, Tarec Christoffer
AU - Bødker, Julie Støve
AU - Schmitz, Alexander
AU - Johansen, Preben
AU - Herold, Tobias
AU - Spiekermann, Karsten
AU - Brown, Jennifer R.
AU - Klitgaard, Josephine L.
AU - Johnsen, Hans Erik
AU - Bøgsted, Martin
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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, naïve, memory, or plasma cell subtypes; the majority falling within the memory (24.5–45.8%) or naïve (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.
AB - 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, naïve, memory, or plasma cell subtypes; the majority falling within the memory (24.5–45.8%) or naïve (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.
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Antineoplastic Agents, Alkylating/therapeutic use
KW - Antineoplastic Agents, Immunological/therapeutic use
KW - B-Lymphocyte Subsets/metabolism
KW - Bone Marrow/metabolism
KW - Cyclophosphamide/therapeutic use
KW - Drug Resistance, Neoplasm/physiology
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - Humans
KW - Leukemia, Lymphocytic, Chronic, B-Cell/classification
KW - Male
KW - Microarray Analysis
KW - Middle Aged
KW - Prognosis
KW - Proof of Concept Study
KW - Retrospective Studies
KW - Rituximab/therapeutic use
KW - Survival Analysis
KW - Time-to-Treatment
UR - http://www.scopus.com/inward/record.url?scp=85043320786&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0193249
DO - 10.1371/journal.pone.0193249
M3 - Journal article
SN - 1932-6203
VL - 13
SP - e0193249
JO - PLOS ONE
JF - PLOS ONE
IS - 3
M1 - e0193249
ER -