Del(6q) in Chronic lymphocytic leukaemia (CLL)

2020-01-01   Liliya Grahlyova , Lubomir Mitev 

1.Military Medical Academy, Department of Cytogenetics and Molecular Biology, Sofia, Bulgaria,


Review on deletion 6q in chronic lymphocytic leukaemia

Clinics and Pathology


Chronic Lymphocytic Leukemia


The deletions of the long arm of chromosome 6 are nonrandom cytogenetic anomalies found in 3 to 7% of cases with chronic lymphocytic leukemia (CLL). To date 163 CLL cases with 6q- are reported. These chromosome anomalies represent a highly heterogeneous group that includes 6q deletions of different lengths and locations. However, the deletion segments overlap some of the bands in 6q and most frequently 6q21, which suggests that in this chromosomal band are located genes or gene responsible for the molecular pathogenesis in a considerable number of cases with 6q- anomaly.


The deletion of 6q is found in 163 cases with CLL (6% of all CLL cases with an abnormal karyotype). Sex ratio of the cases with 6q- is significantly unbalanced, near M:F=2.3:1. The anomaly is observed predominantly in older patients (average age 62.5 years; range 27-90).


The 6q- anomaly is characterized with atypical lymphocyte morphology, CD38 positivity, more extensive lymphadenopathy, and intermediate incidence of IgVH somatic hypermutation (Cuneo A et al., 2004). In cases with 6q deletions have also been found significantly lower hemoglobin concentration, and significantly higher mean age, percent of peripheral prolymphocytes and level of serum lactate dehydrogenase compared with patients without 6q deletion (Stilgenbauer S et al., 1999: Welson MM et al., 2012).


Cases of CLL with deletion of 6q have been shown to require a more demanding treatment regimen (Tsimberidou AM et al., 2007).


It have been suggested that CLL with 6q- comprise an intermediate-risk group and is predictive of shorter survival (Tsimberidou AM et al., 2007, Cuneo et al., 2004 ).


Cytogenetics morphological

Conventional cytogenetic analysis The 6q- anomaly is described in 92 cases as a terminal deletion and in 71 as an interstitial deletion.
The terminal 6q- deletions included the following variants: del(6)(q12) - 2 cases (Brejcha et al., 2014; Mayr et al., 2005), del(6)(q13) - 4 cases (Cuneo et al., 2004; Del Giudiceet al., 2018; Li et al., 2016; Wawrzyniak et al., 2014), del(6)(q14) - 3 cases (Hernandes et al., 1997; Li et al., 2012; Vandenberghe et al., 1992), del(6)(q15) -14 cases (Chena et al., 2003; Cuneo et al., 2004; Fleischman et al., 1989; Haferlach et al., 2007; Juliusson et al., 1985; Lewin et al., 1988; Merup et al., 1994; Reddy, 2006; Travella et al., 2013; Van Roosbroeck et al., 2016; Yunis et al., 1984), del(6)(q16) - 4 cases (Andreieva et al., 2017; Brejcha et al., 2014; Coignet et al., 1996; Vandenberghe et al., 1992), del(6)(q21) - 25 cases (Bernues et al., 2014; Campioni et al., 2012; Chena et al., 2003; Cuneo et al., 2004; Del Giudice et al., 2018; Dicker et al., 2006; Fleischman et al., 1989; Gardiner et al., 1997; Huh et al., 2007; Huh et al., 2011; Lu et al., 2010; Mayr et al., 2006; Offit et al., 1994; Pittman & Catovsky, 1984; Ripolles et al., 2006; Ross & Stockdill 1987; Schlette et al., 2005; Speaks et al., 1992; Travella et al., 2013; Vandenberghe et al., 1992; Wawrzyniak et al., 2014), del(6)(q22) - 2 cases (Nowell et al., 1988; Speaks et al., 1987), del(6)(q23) - 13 cases (Bloomfield et al., 1983; Callet-Bauchu et al., 1996; Crossen et al., 1987; Cuneo et al., 2002; Jarosova et al., 2010; Juliusson et al., 1988; Karakosta et al., 2010; Merup et al., 1994; Pittman & Katovsky, 1984; Sole et al., 1997; Woessner et al., 1996), del(6)(q24) - 6 cases (Andreieva et al., 2017; Barbieri et al., 1984; Einhorn et al., 1989; Merup et al., 1994; Pittman & Katovsky, 1984; Wawrzyniak et al., 2014), del(6)(q25) - 13 cases (Callet-Bauchu et al., 1999; Chena et al., 2003; Pedersen et al., 1994; Pittman & Katovsky, 1984; Sole et al., 1997; Travella et al., 2013).
The interstitial 6q- deletions included the following variants: del(6)(q12q26) - 2 cases (Einn et al., 1998; Huret et al., 1989), del(6)(q12q24) - 2 cases (Callet-Bauchu et al., 1996; Struski et al., 2007), del(6)(q13q15) - 4 cases (Baseggio et al., 2012; Travella et al., 2013; Wlodarska et al., 2007), del(6)(q13q21) -4 cases (Koduru et al., 1997; Morgan et al., 1999; Travella et al., 2013), del(6)(q13q23) - 4 cases (Li et al., 2016; Martin-Subero et al., 2007; Reddy et al., 2006), del(6)(q13q26) - 2 cases (Chapiro et al., 2008; Delhomme-Bachy et al., 1992), del(6)(q14q21) - 2 cases (Lopez et al., 2013; Odero et al., 2001), del(6)(q14q23) - 2 cases (Cuneo et al., 2004; Struski et al., 2007), del(6)(q15q21) - 3 cases (Asoa et al., 1994; Travella et al., 2013; Wawrzyniak et al., 2014), del(6)(q15q22) - 3 cases (Geisler et al., 1997; Put et al., 2009), del(6)(q15q23) - 5 cases (Geisler et al., 1997; Haferlach et al., 2007; Offit et al., 1994; Puiggros et al., 2014; Reddy et al., 2006), del(6)(q14q24) - 2 cases (Lopez et al., 2013; Van Den Neste et al., 2007), del(6)(q15q25) - 3 cases (Callet-Bauchu et al., 1999; Collado et al., 2017; Haferlach et al., 2007), del(6)(q15q22) - 5 cases (El-Taweel et al., 2009; Michaux et al., 1996; Pospisilova et al., 2007; Put et al., 2009; Van den Neste et al., 2007), del(6)(q21q23)- 9 cases (Autio et al., 1987; Cuneo et al., 2004; Geister et al., 1997; Lopes et al., 2012; Merup et al., 1998; Offit et al., 1994; Reddy, 2006; Iravella et al., 2013), del(6)(q21q24)- 2 cases (Brizard et al., 1997; Wren et al., 2010), del(6)(q21q25) - 9 cases (Collado et al., 2017; Delhomme-Bachy et al., 1992; Gardiner et al., 1997; Hamblin et al., 1999; Komatsu et al., 1993; Takashima et al., 1997; Wawrzyniak et al., 2014; Yin et al., 2009), del(6)(q23q25) - 4 cases (Cook et al., 2004; Peterson et al., 1992; Travella et al.,2013, Wong & Chan, 1999), del(6)(q21q27) - 2 cases (Offit et al., 1994), del(6)(q22q26) - 2 cases (Mehes et al., 2006).
In 44 cases (27%) the 6q- is present as sole anomaly, in 16 cases (9.8%) it is associated with one chromosome alteration and in 104 (63.4%) cases it is part of a complex karyotype. These data suggest that the 6q- could be primary, as well as secondary chromosome changes in the clonal evolution of CLL. In most of the cases the clones are hypodiploid, pseudodiploid or hyperdiploid. The most common additional numerical and structural anomalies are +12 (19 cases), +18 (10), -18 (7 cases observed only in cases with a terminal deletion), 13q- (16 cases), 11q- (18 cases) and 17p- (14 cases) and 14q32 rearrangements (21 cases, respectively t(14;18) in 4 cases, t(11;14) in 6 cases, t(8;14) in 3 cases and t(14;19) in 8 cases). The sex chromosomes are involved in chromosome aberrations in 9 cases.

Cytogenetics molecular

Fluorescent in situ hybridization, microarray comparative genome hybridization and exome-sequencing data Using probes mapping the bands 6q21and 6q27 Stilgenbauer S et al., 1999 found that the band 6q21 is deleted in all examined CLL cases with 6q-. Another study with probes mapping the bands 6q16, 6q23, 6q25 and 6q27 revealed that the most frequently deleted regions were at 6q16 and 6q25 (Dalsass et al., 2013). The examinations with array CGH carried out by Jarosova et al., 2017 found three types of 6q deletions: "large deletion" covering the entire 6q, "intermediate" deletion affecting the 6q telomeric region, but not the 6q12 centromeric region and "interstitial" deletions. The latter type deletions were heterogeneous and most of them covered the band 6q21. The authors mapped a minimal deleted region (MDR) (107.7-108.7 Mb) (5 cases) in the band 6q21 where are the genes SCML4, SEC63, OSTM1, NR2E1, SNX3, AFG1L (LACE1) and FOXO3 are located. Using array CGH Urbankova et al., 2014 described a similar MDR comprising a 1.4 Mb region at 6q21 (107.8-109.2 Mb) (2 cases) and Lehmann et al. a deletion of a small segment in 6q21 (107,003,343-107,132,119) (2 cases) in which only the gene CRYBG1 (AIM1) is located. Orgueira et al., 2019 presented exome-sequencing-based copy number aberration in the bands 6q15 (89479426-89563571) (1 case) and 6q21 (110797012-111583801) (1 case). The deleted segment in 6q15 (84kB) included only the gene RNGTT and the deleted segment in 6q21 (787Kb) the genes AMD1, CDK19, RPF2, GTFSC6, SLC16A10 and GSTM2P1.

Genes Involved and Proteins

The existence of multiple 6q- variants that differ in length and localization indicates that the pathogenesis of the 6q- anomaly is complex and is associated with the involvement of different genes. However, it should be noted that pathogenetically the most significant band is 6q21, as it affects more than 70% of the 6q- cases with CLL. In this band an MDR coverage region of approximately 1.4 Kb is reported by two different scientific teams. Jarosova M et al., 2017 demonstrated that of the genes that are localized in the noted region (see above), the genes FOXO3, LACE1, SNX3 and SCML4 have low mRNA expression in CLL cases with 6q- compared to those without the deletion and healthy controls. The authors hypothesized that FOXO3 is the candidate tumor suppressor gene located at the 6q21 region based on its low mRNA expression level, as well as that the reduced pro-apoptotic function of this gene could lead to aberrant overactivation of the phosphoinositol-3-kinase/protein kinase B (PI3K/AKt) cascade and prolonged cell survival (Zhang X et al., 2011). FOXO3 belongs to the forkhead transcription factors that in mammals include also the members FOXO1, FOXO4 and FOXO6 and are characterized by a winged-helix DNA binding motif and forkhead domain (Obsil T & Obsilova V, 2008). Its deregulation has been implicated in different pathological conditions as cardiovascular and neurological diseases, muscle atrophy, premature ovarian failure and tumorigenesis. It is accepted that FOXO3 acts as a tumor suppressor gene in many solid tumors including colon, liver, prostate, bladder and breast cancer. FOXO3 is involved also in numerous cellular processes, such as apoptosis, proliferation, cell cycle progression, DNA damage response and longevity. Considering the important role of FOXO3 in the regulation of DNA damage signaling pathway and that CLL is a disease in which the most common chromosomal abnormalities 13q-, 11q-, +12/12q+ and 17p- affect genes associated with the same pathway, such as MIR-15/16, ATM, MDM2 and TP53, further suggest that FOXO3 could be a major player in the molecular pathogenesis of CLL in the cases with 6q21 deletion. The fact that the ATM and TP53 are downstream targets of FOXO3 and it forms a complex with them to trigger apoptosis upon DNA damage (Chung YM et al, 2012) confirms this assumption. However, in about 30% of cases the band 6q21 is not affected, indicating that besides FOXO3, other genes are also associated with the pathogenesis of 6q- anomaly. Interestingly, in all interstitial 6q- deletions distal from 6q21 and in all terminal 6q- deletions the band 6q25 is involved. In this chromosomal band is located the gene of SOD2 (manganese superoxide dismutase) (6q25.3) that also plays a very important role for cell protection against DNA damage removing superoxide radicals. SOD2 is 23kDa homotetramer - mitochondrial enzyme that dismutates superoxide to hydrogen peroxide. Its transcription is directly stimulated by FOXO3. Deficiencies of SOD2 caused by deletion of 6q25 or mutation of the SOD2 gene are associated with several types of cancer (Oberley et al., 1979; Xu et al; 1999). On the other hand it has been reported that SOD2 reduces tumor development and metastatic ability (Church et al., 1993; Urano et al., 1995; Zhong et al., 1997; Liu et al., 2009). Therefore it has been accepted that SOD2 may act as a tumor suppressor protecting cells from oxidant - induced cancerogenesis. SOD2 is at the bifurcation point between both one-electron (superoxide mediated) and two-electron (hydrogen peroxide mediated) signaling pathways and its activity modulates the levels of both intracellular messengers superoxide anions and hydrogen peroxide. The hydrogen peroxide mediated pathway include the oxidation of phosphatase and tensin homologs deleted on chromosome 10 ( PTEN) by the hydrogen peroxide leading to suppression of its phosphatase activity by formation of a disulfide bond between cysteine residues Cys124 and Cys71 (Lee CU et al., 2015). In a physiological condition this mechanism is responsible for the activation of the PI3K/Act signaling. Oxidized PTEN can be reversibly converted back to its reduced form by the cellular-reducing systems, such as thioredoxin ( TXN) and glutaredoxin ( GLRX) (Lee SR, et al 2002; Schwertassek U et al., 2014), which in turn activates PTEN and subsequently inhibits the PI3K/Act mediated signaling. It is known that the loss of SOD2 results in increased levels of superoxide anion and respectively in enhanced oxidative damage such as membrane lipid peroxidation, protein carbonylation and DNA damage (Elchuri et al., 2005; Yang et al., 2007). It is logical to suppose that the generated by superoxide anion secondary radical species such as OH-, NO2- and CO32- could be relevant for the promotion of B-CLL with 6q25 deletion. These radicals may cause irreversible redox-sensitive inactivation of PTEN by impairing the cellular-reducing systems TXN and GLRX, which will lead to uncontrolled pro-survival signaling of the PI3K/Act pathway.
The data presented above suggest that the deletion of the genes FOXO3 and/or SOD2 in CLL may promote deregulation of DNA damage signaling leading to prolonged cell survival instead of DNA repair or apoptosis.


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Liliya Grahlyova ; Lubomir Mitev

Del(6q) in Chronic lymphocytic leukaemia (CLL)

Atlas Genet Cytogenet Oncol Haematol. 2020-01-01

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