Protein Profiles May Predict Stable, Progressive Chronic Lymphocytic Leukemia

Marilynn Larkin

August 02, 2021

NEW YORK (Reuters Health) — Protein profiles identified through proteomics in early-stage chronic lymphocytic leukemia (CLL) show promise in discriminating between stable and progressive disease, researchers suggest.

As reported in the Journal of Leukocyte Biology, Dr. Cristina Bagacean of CHU de Brest in France explored CLL B-cells' proteomic profile to identify biologic processes affected at an early stage and during disease evolution as stable or progressive.

The team studied 22 purified B cell samples, collected at two time points from four women and seven men with CLL. Patients evolved to either stable or progressive disease.

The stable group was made up of five patients presenting stage Binet A disease for more than 5 years. Sampling was performed at a median age of 68.4 years for the initial time point; the second sample was taken at a median age of 71.4.

Based on the relative abundance levels of 389 differentially expressed proteins (DEPs), samples were separated into stable and progressive clusters, with the main differentiating factor being the RNA splicing pathway.

All stable group patients had good or intermediary prognostic cytogenetic and genetic anomalies, including an isolated deletion of chromosome 13q in three patients, trisomy 12 in two, and a M-IGHV status, indicating a good prognosis.

The other samples were obtained from six progressive CLL patients collected at the early stage of the disease. The median age of the progressive group at first sample collection was 71.5, and at the second, when the disease had progressed, at 73.3.

Four progressive group patients presented with high-risk genetic factors, including two with UM-IGHV (worst prognosis), and two with a complex karyotype.

To test how the DEPs affect RNA splicing, the team conducted an RNA-Seq study that showed 4,217 differentially spliced genes between the two clusters.

Distinct longitudinal evolutions were observed, with mainly proteomic modifications in the stable group and spliced genes in the progressive group.

Specifically, splicing events were six times more frequent in the progressive group. The main aberrant biologic processes controlled by DEPs and spliced genes in that group were cytoskeletal organization, Wnt/beta-catenin signaling, and mitochondrial and inositol phosphate metabolism, with a downstream impact on CLL B-cell survival and migration.

The authors state, "This study suggests that proteomic profiles at the early stage of CLL can discriminate progressive from stable disease and that RNA splicing dysregulation underlies CLL evolution, which opens new perspectives in terms of biomarkers and therapy."

Immunologist Dr. Anil Bamezai of Villanova University, whose expertise is in T-lymphocyte signaling/activation and membrane biology, told Reuters Health by email, "This potentially is a promising approach for predicting CLL disease progression. [It] provides a panoramic view of the cell's interior by detecting and profiling changes in cellular proteins and mRNAs at specific disease stage(s)."

"This is a reasonable first attempt in profiling early-stage CLL patients," he said. "Adding more CLL patients to the study will add power to it. Identifying early signals/triggers that alter protein and mRNA profiles in B cells of progressive CLL patients, I think, will help establish cause and effect, and provide a potential therapeutic target."

Dr. Dequan Xiao, Associate Professor of Chemistry and Director of Center for Integrative Materials at the University of New Haven in Connecticut, also commented by email, "This work...has significantly advanced the pathological understanding of early-stage proteomic events of CLL. In addition, the study pointed to the dysregulated pathways of RNA splicing during the early-stage of CLL, which will inspire medical researchers and clinicians to seek effective drugs or therapeutic solutions by interfering with or correcting these dysregulated pathways."

Dr. Bagacean and PI Dr. Christian Berthou did not respond to requests for a comment.

SOURCE: Journal of Leukocyte Biology, online July 20, 2021