Page 20 - Haematologica May 2020

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Editorials
Genetics of “high-risk” chronic lymphocytic leukemia in the times of chemoimmunotherapy
Alexander Ring and Thorsten Zenz
Department of Medical Oncology and Haematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland E-mail: THORSTEN ZENZ - thorsten.zenz@usz.ch
doi:10.3324/haematol.2020.246504
Chronic lymphocytic leukemia (CLL) is a common leukemic B-cell lymphoma driven by distinct molecular features such as autonomous B-cell receptor signaling and genetic alterations including muta- tions targeting the DNA damage machinery, RNA pro- cessing and splicing, oncogenic signaling pathways (such as Notch) as well as epigenetic and chromatin modifica- tion.1-3 In a simplified model, the “sum” of autonomous B- cell receptor signaling and driver mutations govern CLL progression. In addition, mutations in individual genes, such as TP534,5 are tightly linked to refractoriness to chemotherapy.6 This model summarizes current knowl- edge, but we cannot exclude the possibility that addition- al (maybe unknown) mechanisms contribute significantly to proliferative drive and may thus predispose (or select for?) driver mutations. The current emergence of addi- tional data and more appropriate statistical tools to query complex molecular data can be expected to provide novel insights into the pathogenesis of CLL.7
The study by Jennifer Edelmann and colleagues pub- lished in this issue of Haematologica is an informative addi- tion to the catalogs of gene mutations in CLL. In this study, Edelmann and colleagues use cohorts of patients treated with chemotherapy/alemtuzumab in multiple tri- als and high-resolution single nucleotide polymorphism- array profiling and sequencing to characterize copy num- ber variants and a limited mutational landscape of high- risk CLL cases.8 The analysis summarizes data from 146 patients from CLL trials (CLL8, CLL11, CLL20), in which high risk was defined as either a TP53 deletion/mutation genotype, “complex” karyotype/ increased genomic com- plexity or purine-analog refractory cases (progression-free survival <6 months). The authors thus provide a compre- hensive description of genomic alterations in high-risk CLL patients that are selected for in the context of chemo(immuno)therapy, by building groups and individu- ally testing for unbalanced incidences of mutations. The results lead to a description of well-known tumor drivers, which appear to contribute to high-risk CLL in addition to TP53; MYC, [gain (8)(q24)], CDKN2A/B [del(9)(p21)] and Notch pathway mutations.
The authors describe mutations in Notch-associated genes and known negative regulators (i.e. SPEN, RBPJ). They found that the above genes were mutated/deleted in 3.7-8.2% of high-risk CLL patients and showed that mutated cases had higher levels of expression of Notch target genes (e.g. HES1, DTX1 and MYC). Furthermore, they revealed that SNW1 is a potential negative regulator of the Notch signaling pathway. SNW1 has also been shown to act as a co-activator of Notch-driven transcrip- tion.9
Notch signaling is an evolutionarily conserved signaling pathway that allows cell-cell interactions regulating a wide range of biological functions.10 There are four mammalian
members of NOTCH transmembrane proteins or receptors (NOTCH1 - 4) which have only partially overlapping func- tions despite similar structures. These receptors function as ligand-activated transcription factors, interacting with transmembrane ligands (Delta-like1, 3 and 4, and Jagged1 and 2) (Figure 1A, B).
While Notch signaling plays an important physiological role in hematopoiesis and hematopoietic stem cell biolo- gy,11,12 aberrant Notch signaling has been found to be an oncogenic driver in precursor lymphoid and myeloid neo- plasms as well as mature B-cell neoplasms with different mechanisms of oncogenic pathway activation including mutations in Notch receptors, mutations in negative regu- lators (e.g. FBXW7) or overexpression of ligands and receptors.13-15 NOTCH1 is one of the most frequently mutated genes in CLL,16 affecting approximately 12% of cases.17,18 The majority of mutations occur in coding regions leading to stabilization of the Notch intracellular domain (NICD) via loss of the PEST [proline (P), glutamic acid (E), serine (S), and threonine (T)] domain. NOTCH1 gain-of-function mutations in CLL were first described by Ianni et al.19,20 and were later found in large-scale sequenc- ing studies.21,22 Additionally, mutations in the non-coding 3’ untranslated region have been described.17,23 These mutational events ultimately lead to the accumulation of NCID and increase Notch signaling activity. Notch activa- tion through mechanisms other than activating mutations also frequently occur in CLL.18 with roughly 50% of CLL cases exhibiting high levels of NICD without detectable NOTCH1 mutations.18,20 Although potential mechanisms of NOTCH1 mutation-independent pathway activation have been proposed (e.g. MED12 mutations24), the biology remains incompletely understood. Mutations in the nega- tive regulator FBXW7 have been described in CLL.25
NOTCH1 has been found to be an adverse prognostic marker in CLL26-29 and has been associated with the co- occurrence of other adverse prognostic factors in CLL, such as IGHV mutational status30 and trisomy 12.31 While NOTCH1 mutations are more frequently found in CLL with unmutated IGHV, the accumulation of NICD with- out NOTCH1 mutations seems similarly distributed in CLL with unmutated and mutated IGHV genes.18 Integration of information about the presence or absence of NOTCH1 mutations into prognostic scoring systems improved survival predictions.32 NOTCH1 mutations have not only been linked to progressive disease, but also to the earliest stages of development of CLL.33
Current approaches targeting Notch signaling include γ- secretase inhibitors, which block the proteolytic cleavage of NICD. More than 100 γ-secretase inhibitors have been developed,34 with some demonstrating effects in CLL as single agents or in combination with other drugs.35,36 Monoclonal antibodies targeting Notch receptors (e.g. OMP-52M51) have been tested in pre-clinical37 and clinical
haematologica | 2020; 105(5)