Sµ-3’RRrecHigh Chronic Lymphocytic Leukemia is associated with specific gene expression signature, activation-induced cMYC expression and sustained cell cycle entry.

Abstract

Chronic lymphocytic leukemia (CLL) is an indolent non-Hodgkin B-cell lymphoma and is still incurable. In a previous study of CLL patients, the IGH locus DNA recombination between the switch µ (Sµ) and one 3’ regulatory regions (3’RR), the Sµ-3’RRrec, was detected more frequently than in normal condition. As a reminder, the Sµ-3'RRrec has been repeatedly detected in B-cells of mice and humans and is expected to induce cell death. Sµ-3’RRrec appears to be a rare event in normal B-cells. The Sµ-3’RRrec^High CLLs harboring high count of Sµ-3’RRrec junctions in DNA from blood samples has been characterized as a poor prognosis group with increased MYC expression. In these cases, the increase in Sµ-3'RRrec probably reflects ongoing recombination activity. In order to deepen the molecular basis involved in the IGH recombination process underway in Sµ-3'RRrec^High CLL, we further characterized how the patient groups differ. Our results provide additional features suggesting distinct cellular response to BCR stimulation, different cell signaling and non comparable cell cycle dynamics. Briefly, the Sµ-3'RRrec^High samples appear to retain the ability to respond to BCR stimulation, resulting in increased c-MYC expression and to fast cell cycle entry. Whereas Sµ-3'RRrec^Low CLLs appear to show a lesser response to BCR stimulation and increased Bcl2 transcripts in lymph nodes that could contribute to a more indolent disease. This latter is probably associated with an attenuated genetic recombination activity. Whereas this latter must be exacerbated in condition of more intense proliferation due to MYC in Sµ-3'RRrec^High CLL.