-

-

-

-

40 yrs

M

-

-

-

-

29

9.6

117

75% mature appearing lymphocytes; non-diffuse histopathological pattern.

FAB) B-cell chronic lymphocytic leukemia

CD5, CD19, CD20, CD22, CD25, CD110, CD45, HLDR, CD38 positive, with kappa light chain and sIgM expression.

TRA/D+

B-cell chronic lymphocytic leukemia

12-2013

None

L

12-2013

t bone marrow

24

G-banding

46,XY [10]/46,XY,t(11;14)(q25;q11.2) [10]

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.

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).

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/ Age	Chromosome anomalies	TRA/D status
1.	M	46,XY,inv(14)(q11q13)/45,idem,-12/46,XY,add(10)(q26),del(17)(p12-13)	Not done
2.	F/68	48,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/55	43-46,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,-18	Not done
5.	M/75	46,XY,inv(14)(q11q32)/45,X,-Y	Not done
6.	M/57	46,XY,t(2;10)(q24;q24),inv(14)(q11q32)/46,XY,t(10;14)(q24;q11)	Not done
7.	M	45,X,-Y/47,XY,+Y/48,XY,+Y,+Y/46,XY,inv(14)(q11q32)	Not done
8.	F	46,XX,inv(14)(q11q32)	Not done
9.	M	47,XY,t(6;14)(p12;q11),+12	Not done
10.	M/54	47,XY,+12,del(14)(q11q24)	Not done
11.	F/46	44,X,-X,add(3)(p23),inv(6)(p25q15),-13,t(14;19)(q11;p13)	Not done
12.	M/59	46,XY,add(7)(p15),del(13)(q14)/46,XY,inv(14)(q11q32)	Not done
13.	M/69	46,XY,+8,add(9)(q11),-14,inv(14)(q11q32)/46,idem,add(13)(p11)/ 47,XY,+12	Not done
14.	M/76	46,XY,del(13)(q12q21)/46,idem,del(3)(q21),der(14)t(3;14)(q21;q11)	Not done
15	M/54	46,XY,del(7)(q22q32),t(10;14)(q24;q11)	Not done
16.	F	46,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/56	47,XY,+12,t(14;18)(q32;q21)/47,idem,t(8;14)(q24;q11)	Not done
18.	F/85	46,XX,t(8;14)(q24;q11),?inv(9)(p21q13),del(11)(q13q23),del(13)(q14q22)	TRA/D+
19.	M/71	46,XY,t(8;14)(q24;q11)/46,XY,del(13)(q14q22)	TRA/D+
20.	F	43-46,XX,der(4)t(4;11)(p15-16;q12),add(5)(q35),?der(8)del(8)(p21-22)add(8)(q24),der(9) t(9;17)(q34;q21),-11,-13,-14,del(14)(q11-12q24-31),der(17)del(17)(p13)del(17)(q21),inc
21.	M62	47,XY,t(10;14)(q24;q11),+12	TRA/D+
22.	M/66	46,XY,t(8;14)(q24;q11),del(11)(q13q23)	Not done
23.	M	44,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.