Temporal multiomic modeling reveals a B-cell receptor proliferative program in chronic lymphocytic leukemia

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• B-cell receptor (BCR) signaling is central to mature B-cell lymphomas/leukemias.
• Therapeutic targeting of BCR is limited by mutations.
• Understanding downstream signaling is key for novel therapies.

Purpose of the Study:

• To decipher the cellular program activated downstream of BCR signaling in chronic lymphocytic leukemia (CLL).
• To identify novel therapeutic targets for lymphoid malignancies.

Main Methods:

• Utilized an ex vivo model of BCR-induced proliferation in CLL cells.
• Generated 108 temporal transcriptional and proteomic profiles (1 hour to 4 days).
• Applied mathematical modeling to analyze the temporal response and identify key regulatory genes.

Main Results:

• Identified a structured temporal response with 13,065 transcripts and 4027 proteins.
• Defined a leukemic proliferative signature (430 genes, 374 proteins).
• Uncovered a transcriptional network driven by 14 early genes, including novel players in immune evasion (KMO, IL4I1) and NF-kB modulation (TANK, ROHF).

Conclusions:

• Unveiled the BCR-activated proliferative genetic program in primary leukemic cells.
• The integrated temporal and modeling approach identified new therapeutic targets.
• Findings are relevant for lymphoid malignancies and other cancers driven by ligand-receptor interactions.