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

Abstract

Review on deletion 6q in chronic lymphocytic leukaemia

Keywords

Chromosome 6; Deletion 6q; Chronic lymphocytic leukaemia

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Identity

ICD-Topo	C420,C421,C424
ICD-Morpho	9823/3 Chronic lymphocytic leukaemia /small lymphocytic lymphoma
Atlas_Id	2011

Clinics and Pathology

Disease	Chronic Lymphocytic Leukemia
Note	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.
Epidemiology	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).
Clinics	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).
Treatment	Cases of CLL with deletion of 6q have been shown to require a more demanding treatment regimen (Tsimberidou AM et al., 2007).
Prognosis	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

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), ID: >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 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

Note

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.

Bibliography

Comparison of chromosomal rearrangements in bone marrow cells and blast transformed B-cells in relapse of B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma

Andreieva SV, Korets KV, Ruzhinska OE, Skorokhod IM, Alkhimova OG

Exp Oncol 2017 Jul;39(2):141-144.

PMID 29483496

Japanese B cell chronic lymphocytic leukaemia: a cytogenetic and molecular biological study

Asou H, Takechi M, Tanaka K, Tashiro S, Dohy H, Ohno R, Kamada N

Br J Haematol 1993 Nov;85(3):492-7.

PMID 8136271

Cytogenetic and immunologic characterization of mitotic cells in chronic lymphocytic leukaemia

Autio K, Elonen E, Teerenhovi L, Knuutila S

Eur J Haematol 1987 Oct;39(4):289-98.

PMID 3691755

Cytogenetic evaluation of bone marrow involvement in non-Hodgkin's lymphomas. A survey of 94 cases

Barbieri D, Michaux JL, Bosly A, van Hove W, Noens L, Drochmans A, Louwagie A, Tricot G, Boogaerts M, Vermaelen K

Haematologica May-Jun 1984;69(3):285-96.

PMID 6432640

In non-follicular lymphoproliferative disorders, IGH/BCL2-fusion is not restricted to chronic lymphocytic leukaemia

Baseggio L, Geay MO, Gazzo S, Berger F, Traverse-Glehen A, Ffrench M, Hayette S, Callet-Bauchu E, Verney A, Morel D, Jallades L, Magaud JP, Salles G, Felman P

Br J Haematol 2012 Aug;158(4):489-98.

PMID 22686190

Genetics of lymphocytes influences the emergence of second cancer in chronic lymphocytic leukemia

Bernués M, Durán MA, Puget G, Iglesias J, Galán P, Vercher FJ, Besalduch J, Rosell J

Anticancer Res 2014 May;34(5):2311-4.

PMID 24778036

Nonrandom chromosome abnormalities in lymphoma

Bloomfield CD, Arthur DC, Frizzera G, Levine EG, Peterson BA, Gajl-Peczalska KJ

Cancer Res 1983 Jun;43(6):2975-84.

PMID 6850608

Clonal evolution in chronic lymphocytic leukemia detected by fluorescence in situ hybridization and conventional cytogenetics after stimulation with CpG oligonucleotides and interleukin-2: a prospective analysis

Brejcha M, Stoklasová M, Brychtová Y, Panovská A, Stpanovská K, Vaková G, Plevová K, Oltová A, Horká K, Pospilová S, Mayer J, Doubek M

Leuk Res 2014 Feb;38(2):170-5.

PMID 24246692

11q13 rearrangement in B cell chronic lymphocytic leukemia

Brizard F, Dreyfus B, Guilhot F, Tanzer J, Brizard A

Leuk Lymphoma 1997 May;25(5-6):539-43.

PMID 9250825

dic(4;17)(p11;p11): a new recurrent chromosomal abnormality in chronic B-lymphoid disorders

Callet-Bauchu E, Rimokh R, Tigaud I, Pagès J, Gazzo S, Bastion Y, Sebban C, Magaud JP, Coiffier B, Felman P

Genes Chromosomes Cancer 1996 Nov;17(3):185-90.

PMID 8946198

Cytogenetic and molecular cytogenetic profile of bone marrow-derived mesenchymal stromal cells in chronic and acute lymphoproliferative disorders

Campioni D, Bardi MA, Cavazzini F, Tammiso E, Pezzolo E, Pregnolato E, Volta E, Cuneo A, Lanza F

Ann Hematol 2012 Oct;91(10):1563-77.

PMID 22696050

The most frequent t(14;19)(q32;q13)-positive B-cell malignancy corresponds to an aggressive subgroup of atypical chronic lymphocytic leukemia

Chapiro E, Radford-Weiss I, Bastard C, Luquet I, Lefebvre C, Callet-Bauchu E, Leroux D, Talmant P, Mozziconacci MJ, Mugneret F, Struski S, Raynaud S, Andrieux J, Barin C, Jotterand M, Mossafa H, Ramond S, Terré C, Lippert E, Berger F, Felman P, Merle-Béral H, Bernard OA, Davi F, Berger R, Nguyen-Khac F

Leukemia 2008 Nov;22(11):2123-7.

PMID 18449207

Interphase cytogenetic analysis in Argentinean B-cell chronic lymphocytic leukemia patients: association of trisomy 12 and del(13q14)

Chena C, Arrossagaray G, Scolnik M, Palacios MF, Slavutsky I

Cancer Genet Cytogenet 2003 Oct 15;146(2):154-60.

PMID 14553950

FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage

Chung YM, Park SH, Tsai WB, Wang SY, Ikeda MA, Berek JS, Chen DJ, Hu MC

Nat Commun 2012;3:1000.

PMID 22893124

Increased manganese superoxide dismutase expression suppresses the malignant phenotype of human melanoma cells

Church SL, Grant JW, Ridnour LA, Oberley LW, Swanson PE, Meltzer PS, Trent JM

Proc Natl Acad Sci U S A 1993 Apr 1;90(7):3113-7.

PMID 8464931

Detection of 11q13 rearrangements in hematologic neoplasias by double-color fluorescence in situ hybridization

Coignet LJ, Schuuring E, Kibbelaar RE, Raap TK, Kleiverda KK, Bertheas MF, Wiegant J, Beverstock G, Kluin PM

Blood 1996 Feb 15;87(4):1512-9.

PMID 8608242

Chronic lymphocytic leukemia with isochromosome 17q: An aggressive subgroup associated with TP53 mutations and complex karyotypes

Collado R, Puiggros A, López-Guerrero JA, Calasanz MJ, Larráyoz MJ, Ivars D, García-Casado Z, Abella E, Orero MT, Talavera E, Oliveira AC, Hernández-Rivas JM, Hernández-Sánchez M, Luño E, Valiente A, Grau J, Portal I, Gardella S, Salgado AC, Giménez MT, Ardanaz MT, Campeny A, Hernández JJ, lvarez S, Espinet B, Carbonell F

Cancer Lett 2017 Nov 28;409:42-48.

PMID 28888994

Utility of routine classical cytogenetic studies in the evaluation of suspected lymphomas: results of 279 consecutive lymph node/extranodal tissue biopsies

Cook JR, Shekhter-Levin S, Swerdlow SH

Am J Clin Pathol 2004 Jun;121(6):826-35.

PMID 15198354

Chromosome abnormalities in chronic lymphocytic leukemia revealed by cytochalasin B and Epstein-Barr virus

Crossen PE, Godwin JM, Heaton DC, Tully SM

Cancer Genet Cytogenet 1987 Sep;28(1):93-100.

PMID 3038300

Late appearance of the 11q22.3-23.1 deletion involving the ATM locus in B-cell chronic lymphocytic leukemia and related disorders. Clinico-biological significance

Cuneo A, Bigoni R, Rigolin GM, Roberti MG, Bardi A, Cavazzini F, Milani R, Minotto C, Tieghi A, Della Porta M, Agostini P, Tammiso E, Negrini M, Castoldi G

Haematologica 2002 Jan;87(1):44-51.

PMID 11801464

Chronic lymphocytic leukemia with 6q- shows distinct hematological features and intermediate prognosis

Cuneo A, Rigolin GM, Bigoni R, De Angeli C, Veronese A, Cavazzini F, Bardi A, Roberti MG, Tammiso E, Agostini P, Ciccone M, Della Porta M, Tieghi A, Cavazzini L, Negrini M, Castoldi G

Leukemia 2004 Mar;18(3):476-83.

PMID 14712287

6q deletion detected by fluorescence in situ hybridization using bacterial artificial chromosome in chronic lymphocytic leukemia

Dalsass A, Mestichelli F, Ruggieri M, Gaspari P, Pezzoni V, Vagnoni D, Angelini M, Angelini S, Bigazzi C, Falcioni S, Troiani E, Alesiani F, Catarini M, Attolico I, Scortechini I, Discepoli G, Galieni P

Eur J Haematol 2013 Jul;91(1):10-9.

PMID 23560441

Chromosome studies in stimulated lymphocytes of 50 patients with B-cell chronic lymphocytic leukemia

Delhomme-Bachy M, Bertheas MF, Vasselon C, Calmard-Oriol P, Jaubert J, Rimokh R, Brizard CP, Guyotat D

Nouv Rev Fr Hematol 1992;34(2):175-82.

PMID 1502024

Immunostimulatory oligonucleotide-induced metaphase cytogenetics detect chromosomal aberrations in 80% of CLL patients: A study of 132 CLL cases with correlation to FISH, IgVH status, and CD38 expression

Dicker F, Schnittger S, Haferlach T, Kern W, Schoch C

Blood 2006 Nov 1;108(9):3152-60.

PMID 16840733

Molecular analyses of chromosome 12 in chronic lymphocytic leukemia

Einhorn S, Burvall K, Juliusson G, Gahrton G, Meeker T

Leukemia 1989 Dec;3(12):871-4.

PMID 2586180

Detection of chromosomal abnormalities associated with chronic lymphocytic leukemia: what is the best method?

El-Taweel M, Barin C, Cymbalista F, Eclache V

Cancer Genet Cytogenet 2009 Nov;195(1):37-42.

PMID 19837267

CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life

Elchuri S, Oberley TD, Qi W, Eisenstein RS, Jackson Roberts L, Van Remmen H, Epstein CJ, Huang TT

Oncogene 2005 Jan 13;24(3):367-80.

PMID 15531919

Natural antibodies and immune antibodies of human ABO blood group system

Filitti-Wurmser S

Biochimie 1976;58(11-12):1345-53.

PMID 828062

Secondary abnormalities of chromosome 6q in B-cell chronic lymphocytic leukemia: a sequential study of karyotypic instability in 51 patients

Finn WG, Kay NE, Kroft SH, Church S, Peterson LC

Am J Hematol 1998 Nov;59(3):223-9.

PMID 9798660

Chromosomal characteristics of malignant lymphoma

Fleischman EW, Prigogina EL, Ilynskaya GW, Probatova NA, Konstantinova LN, Kruglova GV, Volkova MA, Osmanov DS

Hum Genet 1989 Jul;82(4):343-8.

PMID 2737667

Cytogenetic, fluorescence in situ hybridisation, and clinical evaluation of translocations with concomitant deletion at 13q14 in chronic lymphocytic leukaemia

Gardiner AC, Corcoran MM, Oscier DG

Genes Chromosomes Cancer 1997 Sep;20(1):73-81.

PMID 9290957

In B-cell chronic lymphocytic leukaemia chromosome 17 abnormalities and not trisomy 12 are the single most important cytogenetic abnormalities for the prognosis: a cytogenetic and immunophenotypic study of 480 unselected newly diagnosed patients

Geisler CH, Philip P, Christensen BE, Hou-Jensen K, Pedersen NT, Jensen OM, Thorling K, Andersen E, Birgens HS, Drivsholm A, Ellegaard J, Larsen JK, Plesner T, Brown P, Andersen PK, Hansen MM

Leuk Res Nov-Dec 1997;21(11-12):1011-23.

PMID 9444933

Refined karyotype-based prognostic stratification of chronic lymphocytic leukemia with a low- and very-low-risk genetic profile

Giudice ID, Rigolin GM, Raponi S, Cafforio L, Ilari C, Wang J, Bordyuh M, Piciocchi A, Marinelli M, Nanni M, Tavolaro S, Filetti M, Bardi A, Tammiso E, Volta E, Negrini M, Saccenti E, Mauro FR, Rossi D, Gaidano G, Guarini A, Rabadan R, Cuneo A, Foà R

Leukemia 2018 Feb;32(2):543-546.

PMID 28924243

Comprehensive genetic characterization of CLL: a study on 506 cases analysed with chromosome banding analysis, interphase FISH, IgV(H) status and immunophenotyping

Haferlach C, Dicker F, Schnittger S, Kern W, Haferlach T

Leukemia 2007 Dec;21(12):2442-51.

PMID 17805327

Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia

Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK

Blood 1999 Sep 15;94(6):1848-54.

PMID 10477713

del(7q) in chronic B-cell lymphoid malignancies

Hernandez JM, Mecucci C, Michaux L, Criel A, Stul M, Meeus P, Wlodarska I, Van Orshoven A, Cassiman JJ, De Wolf-Peeters C, Van den Berghe H

Cancer Genet Cytogenet 1997 Feb;93(2):147-51.

PMID 9078299

The t(14;19)(q32;q13)-positive small B-cell leukaemia: a clinicopathologic and cytogenetic study of seven cases

Huh YO, Abruzzo LV, Rassidakis GZ, Parry-Jones N, Schlette E, Brito-Bapabulle V, Matutes E, Wotherspoon A, Keating MJ, Medeiros LJ, Catovsky D

Br J Haematol 2007 Jan;136(2):220-8.

PMID 17129229

Chronic lymphocytic leukemia with t(14;19)(q32;q13) is characterized by atypical morphologic and immunophenotypic features and distinctive genetic features

Huh YO, Schweighofer CD, Ketterling RP, Knudson RA, Vega F, Kim JE, Luthra R, Keating MJ, Medeiros LJ, Abruzzo LV

Am J Clin Pathol 2011 May;135(5):686-96.

PMID 21502423

Karyotypes of 33 patients with clonal aberrations in chronic lymphocytic leukaemia. Review of 216 abnormal karyotypes in chronic lymphocytic leukaemia

Huret JL, Mossafa H, Brizard A, Dreyfus B, Guilhot F, Xue XQ, Babin P, Tanzer J

Ann Genet 1989;32(3):155-9.

PMID 2817776

Chromosome 6q deletion correlates with poor prognosis and low relative expression of FOXO3 in chronic lymphocytic leukemia patients

Jarosova M, Hruba M, Oltova A, Plevova K, Kruzova L, Kriegova E, Fillerova R, Koritakova E, Doubek M, Lysak D, Prochazka V, Mraz M, Indrak K, Papajik T

Am J Hematol 2017 Oct;92(10):E604-E607.

PMID 28699185

Prognostic information from cytogenetic analysis in chronic B-lymphocytic leukemia and leukemic immunocytoma

Juliusson G, Robèrt KH, Ost A, Friberg K, Biberfeld P, Nilsson B, Zech L, Gahrton G

Blood 1985 Jan;65(1):134-41.

PMID 3871161

Deletion of 5q as a rare abnormality in chronic lymphocytic leukemia

Karakosta M, Tsakiridou A, Korantzis I, Manola KN

Cancer Genet Cytogenet 2010 Jul 15;200(2):175-9.

PMID 20620603

Correlation between mutation in P53, p53 expression, cytogenetics, histologic type, and survival in patients with B-cell non-Hodgkin's lymphoma

Koduru PR, Raju K, Vadmal V, Menezes G, Shah S, Susin M, Kolitz J, Broome JD

Blood 1997 Nov 15;90(10):4078-91.

PMID 9354678

Clonal evolution in chronic lymphocytic leukemia: analysis of correlations with IGHV mutational status, NOTCH1 mutations and clinical significance

López C, Delgado J, Costa D, Villamor N, Navarro A, Cazorla M, Gómez C, Arias A, Muñoz C, Cabezas S, Baumann T, Rozman M, Aymerich M, Colomer D, Pereira A, Cobo F, López-Guillermo A, Campo E, Carrió A

Genes Chromosomes Cancer 2013 Oct;52(10):920-7.

PMID 23893575

Inhalation pharmacokinetics of 1,3-butadiene and 1,2-epoxybutene-3 in rats and mice

Laib RJ, Filser JG, Kreiling R, Vangala RR, Bolt HM

Environ Health Perspect 1990 Jun;86:57-63.

PMID 2401272

Redox Modulation of PTEN Phosphatase Activity by Hydrogen Peroxide and Bisperoxidovanadium Complexes

Lee CU, Hahne G, Hanske J, Bange T, Bier D, Rademacher C, Hennig S, Grossmann TN

Angew Chem Int Ed Engl 2015 Nov 9;54(46):13796-800.

PMID 26418532

Reversible inactivation of the tumor suppressor PTEN by H2O2

Lee SR, Yang KS, Kwon J, Lee C, Jeong W, Rhee SG

J Biol Chem 2002 Jun 7;277(23):20336-42.

PMID 11916965

Molecular allelokaryotyping of early-stage, untreated chronic lymphocytic leukemia

Lehmann S, Ogawa S, Raynaud SD, Sanada M, Nannya Y, Ticchioni M, Bastard C, Kawamata N, Koeffler HP

Cancer 2008 Mar 15;112(6):1296-305.

PMID 18246537

Direct outgrowth of in vivo Epstein-Barr virus (EBV)-infected chronic lymphocytic leukemia (CLL) cells into permanent lines

Lewin N, Aman P, Mellstedt H, Zech L, Klein G

Int J Cancer 1988 Jun 15;41(6):892-5.

PMID 2836321

B-cell lymphomas with MYC/8q24 rearrangements and IGH@BCL2/t(14;18)(q32;q21): an aggressive disease with heterogeneous histology, germinal center B-cell immunophenotype and poor outcome

Li S, Lin P, Fayad LE, Lennon PA, Miranda RN, Yin CC, Lin E, Medeiros LJ

Mod Pathol 2012 Jan;25(1):145-56.

PMID 22002575

The clinical significance of 8q24/MYC rearrangement in chronic lymphocytic leukemia

Li Y, Hu S, Wang SA, Li S, Huh YO, Tang Z, Medeiros LJ, Tang G

Mod Pathol 2016 May;29(5):444-51.

PMID 26916070

Protandim, a fundamentally new antioxidant approach in chemoprevention using mouse two-stage skin carcinogenesis as a model

Liu J, Gu X, Robbins D, Li G, Shi R, McCord JM, Zhao Y

PLoS One 2009;4(4):e5284.

PMID 19384424

Genetic and immunophenotypic profile of IGH@ rearrangement detected by fluorescence in situ hybridization in 149 cases of B-cell chronic lymphocytic leukemia

Lu G, Kong Y, Yue C

Cancer Genet Cytogenet 2010 Jan 1;196(1):56-63.

PMID 19963136

Karyotype complexity and VH gene status in B-cell chronic lymphocytic leukemia

Méhes G, Kovács G, Kajtár B, Lacza A, Várnai A, Losonczy H, Pajor L

Haematologica 2006 Oct;91(10):1430-1.

PMID 16963400

A comprehensive genetic and histopathologic analysis identifies two subgroups of B-cell malignancies carrying a t(14;19)(q32;q13) or variant BCL3-translocation

Martín-Subero JI, Ibbotson R, Klapper W, Michaux L, Callet-Bauchu E, Berger F, Calasanz MJ, De Wolf-Peeters C, Dyer MJ, Felman P, Gardiner A, Gascoyne RD, Gesk S, Harder L, Horsman DE, Kneba M, Küppers R, Majid A, Parry-Jones N, Ritgen M, Salido M, Solé F, Thiel G, Wacker HH, Oscier D, Wlodarska I, Siebert R

Leukemia 2007 Jul;21(7):1532-44.

PMID 17495977

Chromosomal translocations are associated with poor prognosis in chronic lymphocytic leukemia

Mayr C, Speicher MR, Kofler DM, Buhmann R, Strehl J, Busch R, Hallek M, Wendtner CM

Blood 2006 Jan 15;107(2):742-51.

PMID 16179374

A FISH cosmid 'cocktail' for detection of 13q deletions in chronic lymphocytic leukaemia--comparison with cytogenetics and Southern hybridization

Merup M, Jansson M, Corcoran M, Liu Y, Wu X, Rasool O, Stellan B, Hermansson M, Juliusson G, Gahrton G, Einhorn S

Leukemia 1998 May;12(5):705-9.

PMID 9593268

T-cell receptor beta gene rearrangements in leukaemic B-cells from patients with chronic lymphocytic leukaemia: association with chromosome 6 deletions

Merup M, Juliusson G, Hammarström L, Smith CI, Gahrton G

Br J Haematol 1994 Feb;86(2):291-7.

PMID 8199017

BCL3 rearrangement and t(14;19)(q32;q13) in lymphoproliferative disorders

Michaux L, Mecucci C, Stul M, Wlodarska I, Hernandez JM, Meeus P, Michaux JL, Scheiff JM, Noül H, Louwagie A, Criel A, Boogaerts M, Van Orshoven A, Cassiman JJ, Van Den Berghe H

Genes Chromosomes Cancer 1996 Jan;15(1):38-47.

PMID 8824724

PHA/IL2: an efficient mitogen cocktail for cytogenetic studies of non-Hodgkin lymphoma and chronic lymphocytic leukemia

Morgan R, Chen Z, Richkind K, Roherty S, Velasco J, Sandberg AA

Cancer Genet Cytogenet 1999 Mar;109(2):134-7.

PMID 10087947

New Recurrent Structural Aberrations in the Genome of Chronic Lymphocytic Leukemia Based on Exome-Sequencing Data

Mosquera Orgueira A, Antelo Rodríguez B, Díaz Arias J, González Pérez MS, Bello López JL

Front Genet 2019 Sep 20;10:854.

PMID 31616467

Karyotypic stability in chronic B-cell leukemia

Nowell PC, Moreau L, Growney P, Besa EC

Cancer Genet Cytogenet 1988 Jul 15;33(2):155-60.

PMID 3260126

Role of superoxide dismutase in cancer: a review

Oberley LW, Buettner GR

Cancer Res 1979 Apr;39(4):1141-9.

PMID 217531

Structure/function relationships underlying regulation of FOXO transcription factors

Obsil T, Obsilova V

Oncogene 2008 Apr 7;27(16):2263-75.

PMID 18391969

Comparative genomic hybridization and amplotyping by arbitrarily primed PCR in stage A B-CLL

Odero MD, Soto JL, Matutes E, Martin-Subero JI, Zudaire I, Rao PH, Cigudosa JC, Ardanaz MT, Chaganti RS, Perucho M, Calasanz MJ

Cancer Genet Cytogenet 2001 Oct 1;130(1):8-13.

PMID 11672767

Clinical and morphologic features of B-cell small lymphocytic lymphoma with del(6)(q21q23)

Offit K, Louie DC, Parsa NZ, Filippa D, Gangi M, Siebert R, Chaganti RS

Blood 1994 May 1;83(9):2611-8.

PMID 8167342

6q(-) as the only cytogenetic aberration - loss of 6q23 and survival in hematologic malignancies

Pedersen B, Hammoudah S, Jensen P

Int J Oncol 1994 Aug;5(2):321-7.

PMID 21559592

Frequent clonal abnormalities of chromosome band 13q14 in B-cell chronic lymphocytic leukemia: multiple clones, subclones, and nonclonal alterations in 82 midwestern patients

Peterson LC, Lindquist LL, Church S, Kay NE

Genes Chromosomes Cancer 1992 Jun;4(4):273-80.

PMID 1377933

Prognostic significance of chromosome abnormalities in chronic lymphocytic leukaemia

Pittman S, Catovsky D

Br J Haematol 1984 Dec;58(4):649-60.

PMID 6335048

Interstitial del(14)(q) involving IGH: a novel recurrent aberration in B-NHL

Pospisilova H, Baens M, Michaux L, Stul M, Van Hummelen P, Van Loo P, Vermeesch J, Jarosova M, Zemanova Z, Michalova K, Van den Berghe I, Alexander HD, Hagemeijer A, Vandenberghe P, Cools J, De Wolf-Peeters C, Marynen P, Wlodarska I

Leukemia 2007 Sep;21(9):2079-83.

PMID 17525729

Interstitial 13q14 deletions detected in the karyotype and translocations with concomitant deletion at 13q14 in chronic lymphocytic leukemia: different genetic mechanisms but equivalent poorer clinical outcome

Puiggros A, Venturas M, Salido M, Blanco G, Fernandez-Rodriguez C, Collado R, Valiente A, Ruiz-Xivillé N, Carrió A, Ortuño FJ, Luño E, Calasanz MJ, Ardanaz MT, Pin M, Talavera E, González MT, Ortega M, Marugán I, Ferrer A, Gimeno E, Bellosillo B, Delgado J, Hernández J, Hernández-Rivas JM, Espinet B, ,

Genes Chromosomes Cancer 2014 Sep;53(9):788-97.

PMID 24915757

Translocation t(14;18) is not associated with inferior outcome in chronic lymphocytic leukemia

Put N, Meeus P, Chatelain B, Rack K, Boeckx N, Nollet F, Graux C, Van Den Neste E, Janssens A, Madoe V, Van Hoof A, Bilhou-Nabera C, Wlodarska I, Vandenberghe P, Michaux L

Leukemia 2009 Jun;23(6):1201-4.

PMID 19295547

Chronic lymphocytic leukaemia profiled for prognosis using a fluorescence in situ hybridisation panel

Reddy KS

Br J Haematol 2006 Mar;132(6):705-22.

PMID 16487171

Genetic abnormalities and clinical outcome in chronic lymphocytic leukemia

Ripollés L, Ortega M, Ortuño F, González A, Losada J, Ojanguren J, Soler JA, Bergua J, Coll MD, Caballín MR

Cancer Genet Cytogenet 2006 Nov;171(1):57-64.

PMID 17074592

Clonal chromosome abnormalities in chronic lymphocytic leukemia patients revealed by TPA stimulation of whole blood cultures

Ross FM, Stockdill G

Cancer Genet Cytogenet 1987 Mar;25(1):109-21.

PMID 3802050

Expression of bcl-3 in chronic lymphocytic leukemia correlates with trisomy 12 and abnormalities of chromosome 19

Schlette E, Rassidakis GZ, Canoz O, Medeiros LJ

Am J Clin Pathol 2005 Mar;123(3):465-71.

PMID 15716244

Reactivation of oxidized PTP1B and PTEN by thioredoxin 1

Schwertassek U, Haque A, Krishnan N, Greiner R, Weingarten L, Dick TP, Tonks NK

FEBS J 2014 Aug;281(16):3545-58.

PMID 24976139

Cytogenetic studies in seventy-six cases of B-chronic lymphoproliferative disorders

Solé F, Woessner S, Pérez-Losada A, Florensa L, Montero S, Asensio A, Besses C, Sans-Sabrafen J

Cancer Genet Cytogenet 1997 Feb;93(2):160-6.

PMID 9078302

Chromosomal abnormalities in indolent lymphoma

Speaks SL, Sanger WG, Linder J, Johnson DR, Armitage JO, Weisenburger D, Purtilo D

Cancer Genet Cytogenet 1987 Aug;27(2):335-44.

PMID 3297304

Incidence and clinical significance of 6q deletions in B cell chronic lymphocytic leukemia

Stilgenbauer S, Bullinger L, Benner A, Wildenberger K, Bentz M, Döhner K, Ho AD, Lichter P, Döhner H

Leukemia 1999 Sep;13(9):1331-4.

PMID 10482982

[A cytological, immunophenotypical and cytogenetical study of 136 consecutive cases of B-cell chronic lymphoid hemopathies]

Struski S, Leymarie V, Helias C, Falkenrodt A, Fohrer C, Audhuy B, Lioure B, Moskovtchenko P, Mazurier I, Galoisy AC, Gervais C, Mauvieux L, Herbrecht R, Bergerat JP, Lessard M

Pathol Biol (Paris) 2007 Feb;55(1):59-72.

PMID 16690228

Detection of 14q32.33 translocation and t(11;14) in interphase nuclei of chronic B-cell leukemia/lymphomas by in situ hybridization

Takashima T, Itoh M, Ueda Y, Nishida K, Tamaki T, Misawa S, Abe T, Seto M, Machii T, Taniwaki M

Int J Cancer 1997 Jul 3;72(1):31-8.

PMID 9212219

Structural alterations in chronic lymphocytic leukaemia. Cytogenetic and FISH analysis

Travella A, Ripollés L, Aventin A, Rodríguez A, Bezares RF, Caballín MR, Slavutsky I

Hematol Oncol 2013 Jun;31(2):79-87.

PMID 22961973

Assessment of chronic lymphocytic leukemia and small lymphocytic lymphoma by absolute lymphocyte counts in 2,126 patients: 20 years of experience at the University of Texas M.D. Anderson Cancer Center

Tsimberidou AM, Wen S, O', Brien S, McLaughlin P, Wierda WG, Ferrajoli A, Faderl S, Manning J, Lerner S, Mai CV, Rodriguez AM, Hess M, Do KA, Freireich EJ, Kantarjian HM, Medeiros LJ, Keating MJ

J Clin Oncol 2007 Oct 10;25(29):4648-56.

PMID 17925562

Expression of manganese superoxide dismutase reduces tumor control radiation dose: gene-radiotherapy

Urano M, Kuroda M, Reynolds R, Oberley TD, St Clair DK

Cancer Res 1995 Jun 15;55(12):2490-3.

PMID 7780953

Array-based karyotyping in chronic lymphocytic leukemia (CLL) detects new unbalanced abnormalities that escape conventional cytogenetics and CLL FISH panel

Urbankova H, Papajik T, Plachy R, Holzerova M, Balcarkova J, Divoka M, Prochazka V, Pikalova Z, Indrak K, Jarosova M

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2014;158(1):56-64.

PMID 23073527

Chromosomal translocations independently predict treatment failure, treatment-free survival and overall survival in B-cell chronic lymphocytic leukemia patients treated with cladribine

Van Den Neste E, Robin V, Francart J, Hagemeijer A, Stul M, Vandenberghe P, Delannoy A, Sonet A, Deneys V, Costantini S, Ferrant A, Robert A, Michaux L

Leukemia 2007 Aug;21(8):1715-22.

PMID 17541398

Genomic alterations of the JAK2 and PDL loci occur in a broad spectrum of lymphoid malignancies

Van Roosbroeck K, Ferreiro JF, Tousseyn T, van der Krogt JA, Michaux L, Pienkowska-Grela B, Theate I, De Paepe P, Dierickx D, Doyen C, Put N, Cools J, Vandenberghe P, Wlodarska I

Genes Chromosomes Cancer 2016 May;55(5):428-41.

PMID 26850007

Chromosome 11q rearrangements in B non Hodgkin's lymphoma

Vandenberghe E, De Wolf Peeters C, Wlodarska I, Stul M, Louwagie A, Verhoef G, Thomas J, Criel A, Cassiman JJ, Mecucci C

Br J Haematol 1992 Jun;81(2):212-7.

PMID 1643018

Clonal evolution in CLL patients as detected by FISH versus chromosome banding analysis, and its clinical significance

Wawrzyniak E, Kotkowska A, Blonski JZ, Siemieniuk-Rys M, Ziolkowska E, Giannopoulos K, Robak T, Korycka-Wolowiec A

Eur J Haematol 2014 Feb;92(2):91-101.

PMID 24138550

Molecular detection of 6q deletion in Egyptian patients with B-cell chronic lymphoproliferative disorders

Welson MM, Amin GD, Elnoshokaty HE.

Eg J. Hem 2012:37(2):129-134.

Telomeric IGH losses detectable by fluorescence in situ hybridization in chronic lymphocytic leukemia reflect somatic VH recombination events

Wlodarska I, Matthews C, Veyt E, Pospisilova H, Catherwood MA, Poulsen TS, Vanhentenrijk V, Ibbotson R, Vandenberghe P, Morris TC, Alexander HD

J Mol Diagn 2007 Feb;9(1):47-54.

PMID 17251335

Trisomy 12 is a rare cytogenetic finding in typical chronic lymphocytic leukemia

Woessner S, Solé F, Pérez-Losada A, Florensa L, Vilá RM

Leuk Res 1996 May;20(5):369-74.

PMID 8683974

Cytogenetic abnormalities in chronic B-cell lymphoproliferative disorders in Chinese patients

Wong KF, Chan JK

Cancer Genet Cytogenet 1999 May;111(1):55-60.

PMID 10326592

Cytogenetic investigations of chronic lymphocytic leukemia

Wren C, Moriarty H, Marsden K, Tegg E

Cancer Genet Cytogenet 2010 Apr 15;198(2):155-61.

PMID 20362231

Mutations in the promoter reveal a cause for the reduced expression of the human manganese superoxide dismutase gene in cancer cells

Xu Y, Krishnan A, Wan XS, Majima H, Yeh CC, Ludewig G, Kasarskis EJ, St Clair DK

Oncogene 1999 Jan 7;18(1):93-102.

PMID 9926924

A Measurable increase in oxidative damage due to reduction in superoxide detoxification fails to shorten the life span of long-lived mitochondrial mutants of Caenorhabditis elegans

Yang W, Li J, Hekimi S

Genetics 2007 Dec;177(4):2063-74.

PMID 18073424

Chronic lymphocytic leukemia With t(2;14)(p16;q32) involves the BCL11A and IgH genes and is associated with atypical morphologic features and unmutated IgVH genes

Yin CC, Lin KI, Ketterling RP, Knudson RA, Medeiros LJ, Barron LL, Huh YO, Luthra R, Keating MJ, Abruzzo LV

Am J Clin Pathol 2009 May;131(5):663-70.

PMID 19369625

Recurrent chromosomal defects are found in most patients with non-Hodgkin's-lymphoma

Yunis JJ, Oken MM, Theologides A, Howe RB, Kaplan ME

Cancer Genet Cytogenet 1984 Sep;13(1):17-28.

PMID 6467179

Comparison of effects of two polymorphic variants of manganese superoxide dismutase on human breast MCF-7 cancer cell phenotype

Zhang HJ, Yan T, Oberley TD, Oberley LW

Cancer Res 1999 Dec 15;59(24):6276-83.

PMID 10626823

Akt, FoxO and regulation of apoptosis

Zhang X, Tang N, Hadden TJ, Rishi AK

Biochim Biophys Acta 2011 Nov;1813(11):1978-86.

PMID 21440011

Suppression of the malignant phenotype of human glioma cells by overexpression of manganese superoxide dismutase

Zhong W, Oberley LW, Oberley TD, St Clair DK

Oncogene 1997 Jan 30;14(4):481-90.

PMID 9053845

Citation

This paper should be referenced as such :

Mitev L, Liliya Grahlyova L

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

Atlas Genet Cytogenet Oncol Haematol. in press

On line version : http://AtlasGeneticsOncology.org/Anomalies/Deletion6qCLLID2011.html

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