Therapeutic targets in chronic lymphocytic leukemia

Luca Laurenti, Dimitar G. Efremov

Risultato della ricerca: Contributo in rivistaArticolo in rivista

Abstract

Chronic lymphocytic leukemia (CLL) is a common B cell malignancy and is the most common type of adult leukemia in western countries. It is characterized by the progressive accumulation of autoreactive B lymphocytes that are driven to expand by the combined effects of extrinsic signals generatedbytheBcellreceptor(BCR)andothermicroenvironmentalstimuliandcooperatingintrinsic genetic lesions [1]. Studies conducted over the past two decades have provided important advances in the understanding of the pathogenesis of the disease and have led to the development of novel targeted therapies that have improved patient survival [2,3]. The genetic lesions that underlie CLL are heterogeneous and include gross cytogenetic abnormalities and point mutations [4–6]. The most common genetic defect in CLL is the 13q14 abnormality,whichcanbedetectedin55–65%ofcasesandtypicallyinvolvesthemicroRNAsmir-15/16 and the long noncoding RNA Dleu2. Other relatively common genetic lesions include trisomy 12, deletions and/or inactivating mutations in ATM and BIRC3 (both located on 11q22), deletions and/or inactivating mutations in TP53 (located on 17p13), and mutations in NOTCH1 and SF3B1, each of which are typically detected in 5–20% of the cases at diagnosis. In addition, recurrent genetic lesions in more than 30 other genes have been detected with frequencies ranging from 2–5% of the cases [7]. Most of the affected genes cluster into one of several distinct biological pathways, including cell cycle, DNA damage response, RNA metabolism, and BCR, Toll-like receptor (TLR), Notch and NF-kB signaling. However, the exact mechanisms through which these genetic lesions contribute to CLL developmentandprogressionandtheirrelativeclinicalrelevancearestilllargelyunknownandrequire further study. TheextracellularsignalsthatdriveCLLincludeinteractionswithvariouscellularelementspresent in the lymph node tumor microenvironment, such as T cells, monocyte-derived nurse-like cells and stromal cells [8]. These cells provide proliferation and survival signals to the leukemic B cells by secreting different chemokines and cytokines or by expressing distinct surface receptors or adhesion molecules. In addition, the lymph node is the site where CLL cells are believed to primarily receive growthsignalsinducedbystimulationoftheleukemicBCRswithexternal(auto)antigenorstimulation of the leukemic TLRs with TLR ligands, such as unmethylated DNA [9,10]. The identification of the BCR as a major driving force in CLL prompted the development of multiple drugs that block signaling through this receptor. Most of these drugs target BTK or PI3K, although inhibitors of SYK, SRC family kinases and mammalian target of rapamycin (mTOR) have also demonstrated activity in clinical trials [11]. However, despite the high overall response rates, BCR inhibitors in the vast majority of patients induce only partial responses. In addition, acquired resistance to the BTK inhibitor ibrutinib occurs after prolonged treatment in a substantial proportion of patients, and this is more frequent in patients with TP53 mutations [12,13]. Acquired resistance to ibrutinib has been associated with mutations in BTK or its downstream target PLCG2, which ibrutinib’s capacity to irreversibly bind and inhibit BTK or allow for BTK-independent activation of downstream BCR signaling pathways, respectively [14]. However, these defects are frequently found in only a small fraction of the malignant clones at the time of progression, suggesting that other mechanisms are also involved [15]. Possible mechanisms could include lower dependence on BCR signals of leukemic cells with particular combinations of genetic lesions and/or adoptive changes in thekinomeresultingingreateractivationofcompensatorypathwaysthatsubstitutefortheBCRsignal. Such mechanisms have been shown to account for ibrutinib resistance in other B cell malignancies, but further research is needed to determine whether this is
Lingua originaleEnglish
pagine (da-a)1-4
Numero di pagine4
RivistaCancers
Volume12
DOI
Stato di pubblicazionePubblicato - 2020

Keywords

  • chronic lymphocytic leukemia

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