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(Paper co-edited with the European LeukemiaNet)
Translocation t(11;14)(q25;q11) associated with T-cell receptor alpha/delta gene rearrangement and ATM gene deletion in a patient with B-cell chronic lymphocytic leukaemia.
Written2019-12Adriana Zamecnikova
Kuwait Cancer Control Center, Department of Hematology, Laboratory of Cancer Genetics, Kuwait
Age and sex : 40 year(s) old male patient.
Previous History : no preleukemia
no previous malignant disease
no inborn condition of note
Organomegaly : no hepatomegaly ; no splenomegaly ; no enlarged lymph nodes ; no central nervous system involvement
WBC : 29 x 109/L ; Hb : 9.6 g/dL ; platelets : 117 x 109/L;
Bone marrow : 75% mature appearing lymphocytes; non-diffuse histopathological pattern.
Cyto pathology classification
Phenotype : FAB) B-cell chronic lymphocytic leukemia
Immunophenotype : CD5, CD19, CD20, CD22, CD25, CD110, CD45, HLDR, CD38 positive, with kappa light chain and sIgM expression.
Rearranged Ig Tcr : TRA/D+
Precise diagnosis : B-cell chronic lymphocytic leukemia
Date of diagnosis: 12-2013
Treatment : None
Status : L 12-2013
Sample : t bone marrow ; culture time : 24 h ; banding : G-banding
Results : 46,XY [10]/46,XY,t(11;14)(q25;q11.2) [10]
Other molecular cytogenetics technics : Fluoresce in situ hybridization with LSI 13q14/q34/CEP12, LSI p53/ATM, LSI MLL, LSI IGH/CCND1XT, LSI TRA/D (Abbott Molecular, Vysis,US) on interphase cells and hybridization with whole chromosome 14 probe (Metasystems, Germany) on metaphases.
Other molecular cytogenetics results : Normal signal pattern for LSI 13q14/q34/CEP12, LSI p53, LSI MLL and LSI IGH/CCND1XT. Hybridization with LSI p53/ATM probes revealed normal signal pattern for p53 probe and in 90% of cells 1 signal for the ATM gene. Despite the B-cell lineage of leukemic cells, breakpoint at 14q11 led us to perform further FISH studies to confirm the involvement TRA/D gene in the translocation.
Indeed, hybridization with LSI TRA/D dual color break apart probe on interphase cells showed one normal fusion signal, one apparently smaller fusion signal and an additional green signal of TRA/D in 90% of cells. Subsequent FISH analyses on metaphases revealed that the 3' part of the TRA/D gene is relocated from 14q11.2 to chromosome 11 resulting in a split of TRA/D sequences (Figure 1B). Hybridization with whole chromosome 14 probe (red signal) confirmed the translocation of chromosome 14 sequences from der(14) to chromosome 11 (C). Further hybridization studies with LSI p53/ATM probe showed two normal red signals for p53 in 100 % of cells; however only one green signal of the ATM gene in 90% of cells, indicative of ATM deletion in 90% (Figure 1D).
FIGURE 1 Karyotype of the patient showing the translocation t(11;14)(q25;q11.2) (A). Fluorescence in situ hybridization with LSI TRA/D dual color break apart probe revealing juxtaposition of telomeric TCR sequences to chromosome 11 (B). Hybridization with whole chromosome 14 probe (Metasystems, Germany) showing one normal chromosome 14 and translocation of chromosome 14 sequences (red signal) from der(14) to chromosome 11 (C). Hybridization with LSI p53/ATM probe showing two normal red signals for p53 as well as one green signal of the ATM gene, indicative of the deletion of ATM from cells (D).
Chromosomal rearrangements with 14q11 breakpoints are infrequent in CLL (Table 1). While available data for TRA/D involvement gene in are CLL still scarce; it is likely that TRA/D might be involved in a proportion of already published cases displaying 14q11 rearrangements. Our case confirms, that FISH analyses are necessary when TRA/D rearrangement is suggested, including cases exhibiting B-lymphoid immunophenotype. We described such a case in a patient diagnosed as having B-cell chronic lymphocytic leukemia with TRA/D rearrangment in addition to deletion of the ATM gene. The association between TRA/D rearrangement and ATM gene deletion in our patient is further supported by previous studies demonstrating that ATM is required for normal rearrangement of TRA/D, while ATM deficiency predisposes humans and mice to recurrent chromosome 14 translocations involving TRA/D (Liyanage et al.,2000; Zha et al., 2010). In conclusion, while B-cell CLL with TRA/D rearrangement is an exceedingly rare entity, our findings show that TRA/D activation may not be restricted to T-cell malignancies. The occurrence of TRA/D gene rearrangement in the absence of ATM in our patient may represent a possible distinct mechanism of oncogene activation in ATM-deficient B- lineage cells.
 Sex/ AgeChromosome anomalies

TRA/D status

1.M46,XY,inv(14)(q11q13)/45,idem,-12/46,XY,add(10)(q26),del(17)(p12-13)  Not done 
2.F/6848,XX,+2,+12,dup(14)(q11q2?4)Not done 
3.F/78 44,X,-X,add(1)(p36),add(4)(p16),del(6)(p23),add(7)(q32),i(8)(q10),-9,t(11;14)(q11;q23), del(17)(p11),del(18)(q21)/43,X,-X,add(1),add(4),del(6),add(7),t(7;14)(p13;q11),-8,-9, t(11;14)(q11;q32),del(17),del(18) Not done 
4.M/5543-46,X,-Y,del(2)(p23),del(6)(q21),del(7)(q32),del(11)(q21),-12,+t(12;17) (p11;q11),t(14;14) (q11;q32),-17,-18Not done 
5.M/7546,XY,inv(14)(q11q32)/45,X,-Y Not done 
6.M/5746,XY,t(2;10)(q24;q24),inv(14)(q11q32)/46,XY,t(10;14)(q24;q11)Not done 
7.M45,X,-Y/47,XY,+Y/48,XY,+Y,+Y/46,XY,inv(14)(q11q32)Not done 
8.F46,XX,inv(14)(q11q32)Not done 
9.M47,XY,t(6;14)(p12;q11),+12 Not done 
10. M/5447,XY,+12,del(14)(q11q24)Not done 
11. F/4644,X,-X,add(3)(p23),inv(6)(p25q15),-13,t(14;19)(q11;p13) Not done 
12.  M/5946,XY,add(7)(p15),del(13)(q14)/46,XY,inv(14)(q11q32)Not done 
13.M/6946,XY,+8,add(9)(q11),-14,inv(14)(q11q32)/46,idem,add(13)(p11)/ 47,XY,+12Not done 
14.M/7646,XY,del(13)(q12q21)/46,idem,del(3)(q21),der(14)t(3;14)(q21;q11)  Not done 
15M/5446,XY,del(7)(q22q32),t(10;14)(q24;q11)Not done 
16.F46,XX,del(2)(q33q37)/46,XX,del(13)(q12),del(14)(q11q32),der(15)ins(15;13)(q13;q?q?), der(16)t(13;16)(q?;p11)  Not done 
17.M/5647,XY,+12,t(14;18)(q32;q21)/47,idem,t(8;14)(q24;q11)Not done 
18.F/8546,XX,t(8;14)(q24;q11),?inv(9)(p21q13),del(11)(q13q23),del(13)(q14q22) TRA/D+ 
21.M6247,XY,t(10;14)(q24;q11),+12  TRA/D+ 
22.M/6646,XY,t(8;14)(q24;q11),del(11)(q13q23)Not done 
23.M44,XY,-6,-8,der(12;13)(q10;q10)/43,idem,-17,i(17)(q10)/44,idem,der(19) t(14;19)(q11;p13)Not done 
1. Pittman et al., 1984; 2. Yunis et al.,1984; 3. Bird et al.,1986; 4. Fleischman et al.,1989; 5. Schlegelberger et al.,1989; 6. Delhomme-Bachy et al., 1992; 7.Peterson et al., 1992; 8.Stilgenbauer et al., 1993; 9.Geisler et al., 1997; 10.Hamblin et al., 1999; 11.Wong et al., 1999; 12.Wong et al., 1999; 13. Martin-Subero et al.,2001; 14.Buhmann et al., 2002; 15. Lu et al.,2006; 16. Haferlach et al., 2007; 17.Lau et al., 2008; 18.Put et al., 2012; 19.Put et al., 2012; 20.Wawrzyniak et al., 2014; 21.Shin et al., 2015; 22.Li et al., 2016; 23.Collado et al., 2017.
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This paper should be referenced as such :
A. Zamecnikova
Translocation t(11;14)(q25;q11) associated with T-cell receptor alpha/delta gene rearrangement and ATM gene deletion in a patient with B-cell chronic lymphocytic leukaemia.
Atlas Genet Cytogenet Oncol Haematol. in press
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