Format

Send to

Choose Destination
Am J Hematol. 2017 Aug;92(8):E138-E145. doi: 10.1002/ajh.24778. Epub 2017 Jun 15.

A novel in vivo model for studying conditional dual loss of BLIMP-1 and p53 in B-cells, leading to tumor transformation.

Author information

1
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
2
ASST Spedali Civili di Brescia, Progettazione Ricerca Clinica e Studi di Fase I, Brescia, BS, Italy.
3
Department of Hematology, Kumamoto University, Kumamoto, Japan.
4
Maine Medical Center, University of Maine, Scarborough, Maine.
5
Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Abstract

The tumor suppressors B-lymphocyte-induced maturation protein-1 (BLIMP-1) and p53 play a crucial role in B-cell lymphomas, and their inactivation contributes to the pathogenesis of a wide spectrum of lymphoid malignancies, including diffuse large B-cell lymphomas (DLBCLs). Patients with activated B-cell-like (ABC) DLBCL may present with loss of BLIMP-1, c-Myc over-expression, decreased p53, and poor prognosis. Nevertheless, there is a lack of in vivo models recapitulating the biology of high-grade ABC DLBCL. We therefore aimed to develop an in vivo model aiming to recapitulate the phenotype observed in this cohort of patients. A Cre-Lox approach was used to achieve inactivation of both p53 and BLIMP-1 in murine B-cells. Contextual ablation of BLIMP-1 and p53 led to development of IgM-positive B-cell lymphoma with an aggressive phenotype, supported by c-Myc up-regulation, and accumulation of somatic mutations, as demonstrated by whole exome sequencing. Sensitivity of B-tumor cells to BTK inhibition was demonstrated. This model mirrors what reported in patients with ABC DLBLC, and therefore represents a novel model for studying the biology of ABC-DLBCL harboring the dual loss of BLIMP-1/p53 and c-Myc over-expression.

PMID:
28474779
DOI:
10.1002/ajh.24778
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center