The gene expression signature associated with TP53 mutation/deletion in chronic lymphocytic leukaemia is dominated by the under-expression of TP53 and other genes on chromosome 17p.

In chronic lymphocytic leukaemia (CLL), TP53 mutation and deletion are strongly associated with one another and with adverse clinical outcome. Mutant TP53 protein typically accumulates to high levels and has been reported to have transcriptional regulatory activity distinct from that of wild-type TP53. To investigate whether such an effect is relevant to CLL, carefully balanced primary CLL samples with or without TP53 mutation/deletion were compared for their gene expression profiles using high-density DNA microarrays.

A novel type of p53 pathway dysfunction in chronic lymphocytic leukemia resulting from two interacting single nucleotide polymorphisms within the p21 gene.

The ATM-p53 pathway plays an important role in the biology of chronic lymphocytic leukemia (CLL). Its functional integrity can be probed by exposing CLL cells to ionizing radiation (IR) and measuring levels of p53 protein and one of its transcriptional targets, the cyclin-dependent kinase inhibitor p21. We have previously identified two abnormal p53/p21 response patterns associated with inactivating mutations of TP53 and ATM, respectively.

Basic fibroblast growth factor suppresses p53 activation in the neoplastic cells of a proportion of patients with chronic lymphocytic leukaemia.

p53 is the most frequently inactivated gene in human cancers, reflecting its pivotal role in maintaining genomic integrity. The present study was conducted to explore the possibility that tumour cells with no intrinsic defects of the p53 pathway might nevertheless acquire p53 dysfunction through extrinsic suppression of the pathway by microenvironmental factors. Neoplastic cells from patients with chronic lymphocytic leukaemia (CLL) were cultured in the presence or absence of basic fibroblast growth factor (bFGF) and exposed to ionizing radiation (IR) to induce p53 accumulation.

B-cell receptor translocation to lipid rafts and associated signaling differ between prognostically important subgroups of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a highly heterogeneous disease in which interaction of the malignant cells with antigen is thought to play a key role. Individual CLL-cell clones markedly differ in their ability to respond to B-cell receptor ligation, but the mechanism underlying the frequent hyporesponsiveness is incompletely understood. Our aim was to further clarify the extent and cause of the B-cell receptor signaling abnormality in CLL and to assign pathophysiologic relevance to the presence or absence of B-cell receptor responsiveness.

The ATR-p53 pathway is suppressed in noncycling normal and malignant lymphocytes.

Chronic lymphocytic leukaemia (CLL) results from the accumulation of apoptosis-resistant clonal B cells that are arrested in G0/G1, and is heterogeneous with respect to clinical outcome. An aggressive form of the disease is identified by an impaired p53 response to ionizing radiation (IR). This is associated with inactivating mutations of either p53 or ATM, a regulator of p53 activated by IR-induced DNA damage.

V(H) gene usage differs in germline and mutated B-cell chronic lymphocytic leukemia.

Background And Objectives: Given the prognostic relevance that the identification of mutated and germline subgroups of chronic lymphocytic leukemia (CLL) has recently acquired we set out to analyze in depth individual VH gene usage rearrangements in patients with mutated and germline CLL.

Design And Methods: Using sequence analysis of FR1/JH polymerase chain reaction products, the VH immunoglobulin gene configuration was analyzed in 159 rearranged IgH alleles from 154 CLL patients. Having previously identified a spatial relationship between VH gene usage and JH proximity in patients with acute lymphocytic leukemia (ALL), we performed linear and Poisson regression analysis on patients with germline and mutated CLL against VH rearrangements from normal peripheral blood.

Relationship between p53 dysfunction, CD38 expression, and IgV(H) mutation in chronic lymphocytic leukemia.

Established adverse prognostic factors in chronic lymphocytic leukemia (CLL) include CD38 expression, relative lack of IgV(H) mutation, and defects of the TP53 gene. However, disruption of the p53 pathway can occur through mechanisms other than TP53 mutation, and we have recently developed a simple screening test that detects p53 dysfunction due to mutation of the genes encoding either p53 or ATM, a kinase that regulates p53. The present study was conducted to examine the predictive value of this test and to establish the relationship between p53 dysfunction, CD38 expression, and IgV(H) mutation.