TP53 aberrations in chronic lymphocytic leukemia: an overview of the clinical implications of improved diagnostics

Abstract

Chronic lymphocytic leukemia is associated with a highly heterogeneous disease course in terms of clinical outcomes and responses to chemoimmunotherapy. This heterogeneity is partly due to genetic aberrations identified in chronic lymphocytic leukemia cells such as mutations of TP53 and/or deletions in chromosome 17p [del(17p)], resulting in loss of one TP53 allele. These aberrations are associated with markedly decreased survival and predict impaired response to chemoimmunotherapy thus being among the strongest predictive markers guiding treatment decisions in chronic lymphocytic leukemia. Clinical trials demonstrate the importance of accurately testing for TP53 aberrations [both del(17p) and TP53 mutations] before each line of treatment to allow for appropriate treatment decisions that can optimize patients’ outcomes. The current report reviews the diagnostic methods to detect TP53 disruption better, the role of TP53 aberrations in treatment decisions and current therapies available for patients with chronic lymphocytic leukemia carrying these abnormalities. The standardization in sequencing technologies for accurate identification of TP53 mutations and the importance of continued evaluation of TP53 aberrations throughout initial and subsequent lines of therapy remain unmet clinical needs as new therapeutic alternatives become available.

Multiple myeloma with central nervous system relapse

“…68 Venetoclax is a BCL-2 inhibitor and promotes apoptosis via a TP53 mutation-independent pathway and is of proven efficacy in patients with chronic lymphocytic leukemia (CLL) with del(17p) and/or TP53 mutation. 69 It has also been demonstrated to cross the BBB in CLL and is therefore of potential efficacy in CNS-MM. 70 Several phase III trials are currently underway using venetoclax in patients with RRMM.…”

HIF-1α is over-expressed in leukemic cells from TP53-disrupted patients and is a promising therapeutic target in chronic lymphocytic leukemia

“…Chronic lymphocytic leukemia (CLL) patients with high-risk genomic features such as disruption of the TP53 gene (i.e. del(17p) and TP53 mutations) respond poorly to chemoimmunotherapy and frequently relapse [1][2][3][4][5][6][7][8][9] . Significant advances have been made in the treatment of CLL following the introduction of Bruton tyrosine kinase (BTK) inhibitors 10 .…”

“…We have already reported that HIF-1α is involved in drug resistance mechanisms in patients with unmutated (UM) immunoglobulin heavy chain variable region genes (IGHV) 20 . TP53 gene encodes one of 7 the most well-studied tumour suppressor protein, which is often mutated in cancer, thus promoting cell survival, proliferation and drug resistance 21 . p53 may also play a pivotal role in the regulation of HIF-1α, since in conditions of prolonged hypoxia/anoxia the protein accumulates and promotes HIF-1α destruction 22 .…”

Integrative analyses of single-cell transcriptome and regulome using MAESTRO

“…In contrast, the top MAESTRO-predicted regulators in the CLL2 cluster include TP53 and FOXP1, indicating that CLL2 might represent a distinct malignant cell population. TP53 is a well-known tumor suppressor and is frequently mutated or deleted in CLL patients [ 56 ], while FOXP1 was reported to have an oncogenic role in B cell lymphoma and associated with poor clinical outcome [ 57 , 58 ]. In summary, these results demonstrated MAESTRO’s utility in identifying transcriptional regulators from both scRNA-seq and scATAC-seq datasets in complex samples.…”