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Homozygote breakpoint in 13q14 in a case of chronic lymphocytic leukemia
Homozygote Breakpoint in 13q14 in a Case of Chronic Lymphocytic Leukemia
A h o m o z y g o t e b r e a k p o i n t at the c h r o m o s o m a l level does not i m p l i c a t e a h o m o z y g o t e b r e a k p o i n t at the g e n e level. H o w e v e r , the c o i n c i d e n c e of h a v i n g the two h o m o l o g o u s c h r o m o s o m e s b r o k e n at the s a m e band is s u c h a rare e v e n t that it has p r o m p t e d us to report on a case w i t h this trait. M. J., a 61-year-old m a l e patient, was referred to us in February 1984 for isolated h y p e r l e u t : o c y t o s i s d i s c o v e r e d on a routine h e m o g r a m . H e m o g l o b i n was 16.1 g/dL, WBC was 19 x 10~VI, w i t h 71% l y m p h o c y t e s , platelet c o u n t was 230 :,( I(I~VL. Bone m a r r o w was infiltrated w i t h 55% small l y m p h o c y t e s with m o n o c l o n a l IgS ,k c h a i n e x p r e s s i o n . A c h r o n i c l y m p h o c y t i c l e u k e m i a (CLL) stage A (Binet classification) was d i a g n o s e d . A k a r y o t y p e from the p e r i p h e r a l blood (with LPS, or PWM, or Prot-A, or PMA m i t o g e n s , RHG b a n d i n g , 96 m i t o s e s analyzed) was f o u n d to be normal. Treatm e n t w i t h c h l o r a m b u c i l was instituted in July 1985. L y m p h o c y t o s i s i n c r e a s e d in M a r c h 1989 and the patient was treated w i t h c h l o r a m b u c i l and p r e d n i s o n e . A n e m i a and m o d e r a t e t h r o m b o c y t o p e n i a w e r e first found in February 1990. In April 199(I, h e m o g l o b i n was 9.1 g / d L and platelet (:ount was 40 x I()~VL. A refractory a n e m i a in
F i g u r e I Partial karyotypes (RttG banding) showing t(2:13)(ql?2;q14) and t(12:13)(q2?l:ql?4). Derivative chromosomes 2 and 12 are on the right of each pair, der(13)t(2:13) is on the left. and der(13)t(12;13) is on the right.
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12
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13
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b 231 ':~; 1991 Elstwier Science t ublislrling Co., Inc. 65 fi Avenue of the AIm~ricas, N~:~.~."York, NY 10010
Cancer Genel Cytogenel 57:231 2:~2(1~3911 0165-461)8'01 ,'$03 50
232
J.L. Huret et al. t r a n s f o r m a t i o n (RAEB-t) was d i a g n o s e d on b o n e inarrow smears (blast cells type I and II w e r e 25%). In spite of v a r i o u s treatments, no i m p r o v e m e n t o c c u r r e d . In January 1991. a k a r y o t y p e from the bone m a r r o w w i t h o u t mitogen s t i m u l a t i o n was normal, w h e r e a s the k a r y o t y p e from the p e r i p h e r a l blood (with PHA a l o n e or w i t h P t t A PMA, usual doses, RHG b a n d i n g , 53 mitoses analyzed] was 46,XY (37 initoses).; 46.XY,t(2;13){q1?2:q14),t(12:13)(q2?1;q1?4) [16 mitoses}, w h e r e both (:hronmsomes 13 w e r e f o u n d i n v o h , ed in two different transhx:ations. T h e b r e a k p o i n t s on c h r o m o s o m e s 13 apt)eared to be located at the s a m e band. T h i s karyotype w i t h PHA or PHA + P M A r e p r e s e n t s the k a r y o t y p e of the CLL, as p r e v i o u s l y s h o w n [1]. H o w a h o m o z y g o t e b r e a k p o i n t can o c c u r is u n k n o w n , but a few h y p o t h e s e s (:an be made. T h e y c o u h t arise 1 } by c h a n c e , and s o m e at least c e r t a i n l y do. T h i s situation w o u l d be favored if the b r e a k p o i n t s oc(:ur in 2} a " b r e a k a b l e " z o n e (e.g., fragile site), or in 3) a r e a r r a n g e m e n t - p r o n e sequen(:e (e.g., i m m u n o g l o b u l i n gene, i n a s m u c h as it is k n o w n that, w h e n the rearranged first allele is not fun(:tional, the s e c o n d allele is t h e n rearranged). Finally. 4} a h o m o z y g o t e b r e a k p o i n t o c c u r r i n g w i t h i n a r e c e s s i v e a n t i o n c o g e n e w o u l d not be p a r t i c u l a r l y favored, but its occurren(:e w o u l d , in return, (:ause or favor a inaligilant disease. It has re(:entlv been ret)orted that a prot)ortion of CLL patients with or v,'ithout a p p a r e n t 13q14 i n v o l v e m e n t [2, 3]. as ,.veil as other l e u k e m i c patients [4.5, 6], exhibit i m p a i r e d r e t i n o b l a s t o m a genes {RB). As the 13q14 a n o m a l i e s in the present report w e r e found 7 years after the d i a g n o s i s of CI,I,, a h y p o t h e t i c ina(:tivation of the RB genes c o u h t be related w i t h the progression of the d i s e a s e ( l y m p h o c y t e s w e r e 80 × lO%'L in Apri11990). The s t u d y of RB in our patient w i t h a h o m o z y g o t e breakt)oirlt in 1:'t(t14 is being undertakeiL H o l n o z y g o t e b r e a k p o i n t s s h o u l d be t)ublished as su(:h, as they are perhat)s nonrand o m l y d i s t r i b u t e d , p o i n t i n g to specific ( ' h r o m o s o m e hands. S o m e of these st)e(:ifi(: h a n d s c o u l d carry n n k n o w n r e c e s s i v e antion(:ogenes or o t h e r sequen(:e.s of interest in (:ar(:inogenesis. The authors thank Elizabeth tIuret-Ward for help with translation and Martine Putiron for te.(:hnical assistance.. This work was st,t)ported by Association pour la Re(:herche stir le Cancer and Liguc Natiunale. contre le Cancer. J. L. H U R E T A. BRIZARD B. D R E Y F U S J. T A N Z E R
D~.t)artement d - H e m a t o l o g i e et O n c o l o g i e M e d i c a l e H6pital Jean Bernard F-86021 Poitiers, France
REFERENCES 1. Mossafa H. Huret JL. Mossalayi MD. Brizard A. Tanzer J (1989}: Use of various mitogens and cell stimulation index in 21 patients with (:hroni(: lymphocytic leukaemia. Ann Gene.t 32:152-154. 2. Oscier D, Chapman R, l:itchett M, Cowc[l [ (1990]: Deletion of a retinoblastoma gene in B cell (:hrollic lymphocytic leukemia. Blood 76. suppl.1:956. 3. Peterson I,C, l,indquisl I,, Kay NE [1990}: l,oss of tumor suppressor genes (13q14). (:lona[ and non clonal c:ytogenetic abnormalities, and karyotypic evolution in B-chronic lymphocytic leukemia (CI,I,}. Blood 76, suppl. 1:1223. 4. (;insberg A. Raffeld M. Cossman J (1990): Inactivation of the retinoblastoma gene in human lymphoid neoplasms. Blood 76. suppl. 1:914. 5. Lebowitz P. Papac R, Ghosh PK (1990]: Impaired re.tinoblastoma (Rb} gene expression in agnogenic myeloid metaplasia (AMM}. Blood 76. suppl. 1:9:.16. 6. Furukawa Y. lshida Y. Belvin M. De Caprio JA, (.;riffin JD (1990): Abnormalities in expression of the product of the retinoblastoma susceptibility gene in primary human h.'ukemias. Blond 76, suppl. I:1079
A h o m o z y g o t e b r e a k p o i n t at the c h r o m o s o m a l level does not i m p l i c a t e a h o m o z y g o t e b r e a k p o i n t at the g e n e level. H o w e v e r , the c o i n c i d e n c e of h a v i n g the two h o m o l o g o u s c h r o m o s o m e s b r o k e n at the s a m e band is s u c h a rare e v e n t that it has p r o m p t e d us to report on a case w i t h this trait. M. J., a 61-year-old m a l e patient, was referred to us in February 1984 for isolated h y p e r l e u t : o c y t o s i s d i s c o v e r e d on a routine h e m o g r a m . H e m o g l o b i n was 16.1 g/dL, WBC was 19 x 10~VI, w i t h 71% l y m p h o c y t e s , platelet c o u n t was 230 :,( I(I~VL. Bone m a r r o w was infiltrated w i t h 55% small l y m p h o c y t e s with m o n o c l o n a l IgS ,k c h a i n e x p r e s s i o n . A c h r o n i c l y m p h o c y t i c l e u k e m i a (CLL) stage A (Binet classification) was d i a g n o s e d . A k a r y o t y p e from the p e r i p h e r a l blood (with LPS, or PWM, or Prot-A, or PMA m i t o g e n s , RHG b a n d i n g , 96 m i t o s e s analyzed) was f o u n d to be normal. Treatm e n t w i t h c h l o r a m b u c i l was instituted in July 1985. L y m p h o c y t o s i s i n c r e a s e d in M a r c h 1989 and the patient was treated w i t h c h l o r a m b u c i l and p r e d n i s o n e . A n e m i a and m o d e r a t e t h r o m b o c y t o p e n i a w e r e first found in February 1990. In April 199(I, h e m o g l o b i n was 9.1 g / d L and platelet (:ount was 40 x I()~VL. A refractory a n e m i a in
F i g u r e I Partial karyotypes (RttG banding) showing t(2:13)(ql?2;q14) and t(12:13)(q2?l:ql?4). Derivative chromosomes 2 and 12 are on the right of each pair, der(13)t(2:13) is on the left. and der(13)t(12;13) is on the right.
.[-,2
12
•
,.
13
-j-t-
b 231 ':~; 1991 Elstwier Science t ublislrling Co., Inc. 65 fi Avenue of the AIm~ricas, N~:~.~."York, NY 10010
Cancer Genel Cytogenel 57:231 2:~2(1~3911 0165-461)8'01 ,'$03 50
232
J.L. Huret et al. t r a n s f o r m a t i o n (RAEB-t) was d i a g n o s e d on b o n e inarrow smears (blast cells type I and II w e r e 25%). In spite of v a r i o u s treatments, no i m p r o v e m e n t o c c u r r e d . In January 1991. a k a r y o t y p e from the bone m a r r o w w i t h o u t mitogen s t i m u l a t i o n was normal, w h e r e a s the k a r y o t y p e from the p e r i p h e r a l blood (with PHA a l o n e or w i t h P t t A PMA, usual doses, RHG b a n d i n g , 53 mitoses analyzed] was 46,XY (37 initoses).; 46.XY,t(2;13){q1?2:q14),t(12:13)(q2?1;q1?4) [16 mitoses}, w h e r e both (:hronmsomes 13 w e r e f o u n d i n v o h , ed in two different transhx:ations. T h e b r e a k p o i n t s on c h r o m o s o m e s 13 apt)eared to be located at the s a m e band. T h i s karyotype w i t h PHA or PHA + P M A r e p r e s e n t s the k a r y o t y p e of the CLL, as p r e v i o u s l y s h o w n [1]. H o w a h o m o z y g o t e b r e a k p o i n t can o c c u r is u n k n o w n , but a few h y p o t h e s e s (:an be made. T h e y c o u h t arise 1 } by c h a n c e , and s o m e at least c e r t a i n l y do. T h i s situation w o u l d be favored if the b r e a k p o i n t s oc(:ur in 2} a " b r e a k a b l e " z o n e (e.g., fragile site), or in 3) a r e a r r a n g e m e n t - p r o n e sequen(:e (e.g., i m m u n o g l o b u l i n gene, i n a s m u c h as it is k n o w n that, w h e n the rearranged first allele is not fun(:tional, the s e c o n d allele is t h e n rearranged). Finally. 4} a h o m o z y g o t e b r e a k p o i n t o c c u r r i n g w i t h i n a r e c e s s i v e a n t i o n c o g e n e w o u l d not be p a r t i c u l a r l y favored, but its occurren(:e w o u l d , in return, (:ause or favor a inaligilant disease. It has re(:entlv been ret)orted that a prot)ortion of CLL patients with or v,'ithout a p p a r e n t 13q14 i n v o l v e m e n t [2, 3]. as ,.veil as other l e u k e m i c patients [4.5, 6], exhibit i m p a i r e d r e t i n o b l a s t o m a genes {RB). As the 13q14 a n o m a l i e s in the present report w e r e found 7 years after the d i a g n o s i s of CI,I,, a h y p o t h e t i c ina(:tivation of the RB genes c o u h t be related w i t h the progression of the d i s e a s e ( l y m p h o c y t e s w e r e 80 × lO%'L in Apri11990). The s t u d y of RB in our patient w i t h a h o m o z y g o t e breakt)oirlt in 1:'t(t14 is being undertakeiL H o l n o z y g o t e b r e a k p o i n t s s h o u l d be t)ublished as su(:h, as they are perhat)s nonrand o m l y d i s t r i b u t e d , p o i n t i n g to specific ( ' h r o m o s o m e hands. S o m e of these st)e(:ifi(: h a n d s c o u l d carry n n k n o w n r e c e s s i v e antion(:ogenes or o t h e r sequen(:e.s of interest in (:ar(:inogenesis. The authors thank Elizabeth tIuret-Ward for help with translation and Martine Putiron for te.(:hnical assistance.. This work was st,t)ported by Association pour la Re(:herche stir le Cancer and Liguc Natiunale. contre le Cancer. J. L. H U R E T A. BRIZARD B. D R E Y F U S J. T A N Z E R
D~.t)artement d - H e m a t o l o g i e et O n c o l o g i e M e d i c a l e H6pital Jean Bernard F-86021 Poitiers, France
REFERENCES 1. Mossafa H. Huret JL. Mossalayi MD. Brizard A. Tanzer J (1989}: Use of various mitogens and cell stimulation index in 21 patients with (:hroni(: lymphocytic leukaemia. Ann Gene.t 32:152-154. 2. Oscier D, Chapman R, l:itchett M, Cowc[l [ (1990]: Deletion of a retinoblastoma gene in B cell (:hrollic lymphocytic leukemia. Blood 76. suppl.1:956. 3. Peterson I,C, l,indquisl I,, Kay NE [1990}: l,oss of tumor suppressor genes (13q14). (:lona[ and non clonal c:ytogenetic abnormalities, and karyotypic evolution in B-chronic lymphocytic leukemia (CI,I,}. Blood 76, suppl. 1:1223. 4. (;insberg A. Raffeld M. Cossman J (1990): Inactivation of the retinoblastoma gene in human lymphoid neoplasms. Blood 76. suppl. 1:914. 5. Lebowitz P. Papac R, Ghosh PK (1990]: Impaired re.tinoblastoma (Rb} gene expression in agnogenic myeloid metaplasia (AMM}. Blood 76. suppl. 1:9:.16. 6. Furukawa Y. lshida Y. Belvin M. De Caprio JA, (.;riffin JD (1990): Abnormalities in expression of the product of the retinoblastoma susceptibility gene in primary human h.'ukemias. Blond 76, suppl. I:1079