t(16;21)(p11.2;q22): A Recurrent Primary Rearrangement in ANLL R. Morgan, C. B. Riske, A. Meloni, C. A. Ries, C. H. Johnson, R. S. Lemons, and A. A. Sandberg
ABSTRACT: We have identified three patients with acute nonlvmphaeyti(: leukemia (ANLI,), suI)types M2. M4. and M7, who had a t116:21)(p11.2:q221 in the affected (:ells. There are six previotlsly reported cases oj ANLL with the same tl16:2t ). The t{6:211 should thereJ'ore be ia(:hlded as another primary rearrangement in ANLL. Follow-up of these cases, though still limited, saggests a poor prognosis, as most patients have achieved a (:linical remission but aaly jot a shart duration. INTRODUCTION M y e l o i d n e o p l a s i a s , p r e s e n t i n g as l e u k e m i a s or t r a n s f o r m e d m y e l o d y s p l a s t i c a n d m y e l o p r o l i f e r a t i v e d i s o r d e r s , h a v e b e e n c h a r a c t e r i z e d by s p e c i f i c c y t o g e n e t i c rea r r a n g e m e n t s . T w e n t y - s i x s p e c i f i c or p r i m a r y c h r o m o s o m e t r a n s l o c a t i o n s h a v e b e e n r e p o r t e d w i t h i n t h e s e m y e l o i d h e m a t o l o g i c d i s o r d e r s [1]. T h e m a j o r i t y (15 of 26) o c c u r i n v a r i o u s c a s e s of a c u t e n o n l y m p h o c y t i c l e u k e m i a (ANLL) w i t h d i f f e r e n t FAB c l a s s i f i c a t i o n s . T h e o t h e r e l e v e n h a v e b e e n a s s o c i a t e d w i t h specific FAB s u b t y p e s . S i m i l a r l y to t h e e l e v e n t r a n s l o c a t i o n s t h a t are f o u n d in m o r e t h a n o n e FAB g r o u p , t h e t(16:21) h a s b e e n i d e n t i f i e d in t h r e e d i f f e r e n t FAB t y p e s a n d m a y i n w ) l v e a m u l t i p o t e n t s t e m cell [21. O n l y six c a s e s w i t h t h e t(16;21) h a v e b e e n p r e v i o u s l y r e p o r t e d [3 6] a n d all b a d ANLL (Table 11. W e p r e s e n t t h r e e a d d i t i o n a l cases a n d suggest t h a t t ( 1 6 : 2 1 ) ( p 1 1 . 2 : q 2 2 ) w a r r a n t s r e c o g n i t i o n as a n o t h e r p r i m a r y r e a r r a n g e m e n t in m y e l o i d l e u k e m i a . All t h r e e c a s e s h a d a c o m p l e t e r e m i s s i o n f o l l o w i n g c h e m o t h e r a p y . H o w e v e r , at least ()he p a t i e n t s u r v i v e d less t h a n a y e a r f o l l o w i n g r e m i s s i o n . CASE H I S T O R I E S
Case 1 A 2 1 - y e a r - o l d C h i n e s e m a l e p r e s e n t e d in J a n u a r y 1989 w i t h p e t e c h i a e . T h e h e m a t o logic f i n d i n g s at p r e s e n t a t i o n are s h o w n in T a b l e 2. After RBC a n d p l a t e l e t t r a n s f u s i o n s , l a b o r a t o r y d a t a i n c l u d e d a W B C of 2.1 × lO:~/mm :~, Hb 9.1 g/dl, M C V 97 fl, a n d From the Cancer Center of Southwest Biomedical Research Institute and Genetrix, In(:. [R. M.. C. B. R., A. M.. A. A. S.), Scottsdale, Arizona: LICSF Medical Center. lh~matoh~gyClinic (C. A. R.), San Francisco, California; Maricopa Medical Center (C. 11. ].). Phoenix. Ariznna: and University of Utah Medical Ccnh~r. Primary Children's Medical (;enter (R. S. L.). Salt l,ake City, l.ltah. Address reprint requests to: Dr. A. A. Sandberg, The Cancer Center oj Southwest Biomedical Research Institute and Genetrix, Inc.. 6401 E. Thomas Road. Scottsdale, Arizona 85251. Received July 16, 1990: accepted August 24, 1990.
83 ¢~ 1991 Elsevier Science Publishing Co., lnc, 655 Avenue of the Americas, New York, NY 10010
Cancer Genet Cytogenet 53:83 90 (1991) 0165-4608/91/$03.51)
84
R. Morgan et al.
Table 1
Karyotype of published cases with a t(16;21)(p11.2;q22.3)
Patient
Karyotype
No. cells
1 .(~
46,XY 46,XY,t(16;21)(pl 1.2;q22.3) 46,XX,del(9)(q12q22),t(16;21)(p11.2;q22.3) 47,XX,del(9)(q12q22),t(16;21)(p11.2q:22.3), + 10 46,XY 45,XY,- 2, + der(2)t(1;2)(q25;q33), - 16,- 21, + der(21)t(16;21)(pll.2:q22) 45,XY,- 2, + der(2)t(1:2)(q25;q33),t(4:6)(p14;q11), del(15)(q11.2q15), 16, 21.+der(21)t(16;21)(pll.2;q22) 46,XY,ins(7;2)(q11;p14p23),t(16;21)(p11;q22) 46,XY,t(16;21 )(pl 1:q22) 46,XY,t(16;21)(p11;q22)/45,XY,- 9,t(16:21)(p11;q22) 46,XX,t(16;21)(p11:q22)/47,XX,t(16;21)(p11;q22), + 10 46,XY,t(16;21}(p12-pl 3;q22] t(16;21)(p11;q22),t(3;11)(q29;p11), 6, + der{6)t(1 ;6)(q23;p25) t(16;21)(pl 1;q22)/t( 16;21)(p 11 ;q22),t(13;18)
1 14 6 9 1 2
2.~ 3.¢~
'~ P a l i e n t is d i s c u s s e d ~' N u m b e r
Reference
12 36 6 13 27 8 -- h h
141 141 161 13l 15] 15l
in l h i s r e p o r t .
of c e i l s w a s n o t a v a i l a b l e .
platelets 100 × 10:Umm:L A bone marrow aspirate showed normoblastic erythroid hypoplasia, granulocytic hypoplasia and decreased megakaryocytes, and 70% blasts with a reversed nuclear/cytoplasmic ratio, prominent nucleoli, and agranular cytoplasm. Some blasts showed erythrophagocytosis. The bone marrow biopsy showed 80% cellularity, 70% abnormal cells, normoblastic erythroid hypoplasia, and decreased megakaryocytes. The blasts had a large amount of cytoplasm with prominent granules and were peroxidase, chloroacetate esterase (CAE) and butyrate esterase negative. The III A stain for megakaryocytes was strongly positive ( + ) and the (:ell surface markers LN3, Leu4, and Leu M-1 were all negative. Based on the strong positivity of the megakaryocyte marker, Anti III A, the diagnosis of acute megakaryocytic leukemia (FAB classification M7) was established. The peroxidase, CAE, and butyrate esterase stains of the patient's blast cells were all negative, thereby excluding all other subgroups of AML, specifically M4. T- and B-cell markers were also negative. The patient was treated with high-dose cytarabine and mitoxantrone and remained in complete remission for 3 months during which time his bone marrow was harvested with plans for an autologous bone marrow transplant. The patient relapsed at 5 months and was reinducted witb high-dose etoposide and high-dose cytarabine. An autologous bone marrow transplant was performed after a second complete remission. The patient then relapsed again and died one year after presentation.
Case 2
A 33-year-old white female reported cramping abdominal pain, vomiting, easy bruisability, bleeding gums, and weakness for the previous 2 months. On the day of admission she suffered a syncopal episode. At initial presentation, she was hypotensive with a nonpalpable pnlse. Vital signs stabilized with administration of IV fluids and packed red blood cells. Examination disclosed a thin female in marked distress. Pertinent findings included hypoactive bowel sounds and a firm and diffusely tender abdomen. The stool was brown but positive for occult blood. Gums showed no hypertrophy or bleeding,
2
11.5 12.4 10.2
7.1 7.3
Hb
33.7
22
Hct
Hematological
97 114.5
MCV
findings
3.0 23.3 17.94 21.6 14.1 6.4
WBC
13
7
10
Ne 20 61 63 71 72 67
BI 10 52 188 70 72 22
P1 70 30 14 2 9 8
Ly
of all cases
Peripheral blood
at presentation
1
0 8
Met
involving
1
0
Eos 0 0 12 16 9 3
Mo 80 90 55 + N
Cel 70 + 57 47 53.2 80 +
BI
a t(16;21)(p11.2;q22.3)
19.2 19.4
0
Mo
30
EMM
Bone marrow
8.2 2.4
ABSTRACT: We have identified three patients with acute nonlvmphaeyti(: leukemia (ANLI,), suI)types M2. M4. and M7, who had a t116:21)(p11.2:q221 in the affected (:ells. There are six previotlsly reported cases oj ANLL with the same tl16:2t ). The t{6:211 should thereJ'ore be ia(:hlded as another primary rearrangement in ANLL. Follow-up of these cases, though still limited, saggests a poor prognosis, as most patients have achieved a (:linical remission but aaly jot a shart duration. INTRODUCTION M y e l o i d n e o p l a s i a s , p r e s e n t i n g as l e u k e m i a s or t r a n s f o r m e d m y e l o d y s p l a s t i c a n d m y e l o p r o l i f e r a t i v e d i s o r d e r s , h a v e b e e n c h a r a c t e r i z e d by s p e c i f i c c y t o g e n e t i c rea r r a n g e m e n t s . T w e n t y - s i x s p e c i f i c or p r i m a r y c h r o m o s o m e t r a n s l o c a t i o n s h a v e b e e n r e p o r t e d w i t h i n t h e s e m y e l o i d h e m a t o l o g i c d i s o r d e r s [1]. T h e m a j o r i t y (15 of 26) o c c u r i n v a r i o u s c a s e s of a c u t e n o n l y m p h o c y t i c l e u k e m i a (ANLL) w i t h d i f f e r e n t FAB c l a s s i f i c a t i o n s . T h e o t h e r e l e v e n h a v e b e e n a s s o c i a t e d w i t h specific FAB s u b t y p e s . S i m i l a r l y to t h e e l e v e n t r a n s l o c a t i o n s t h a t are f o u n d in m o r e t h a n o n e FAB g r o u p , t h e t(16:21) h a s b e e n i d e n t i f i e d in t h r e e d i f f e r e n t FAB t y p e s a n d m a y i n w ) l v e a m u l t i p o t e n t s t e m cell [21. O n l y six c a s e s w i t h t h e t(16;21) h a v e b e e n p r e v i o u s l y r e p o r t e d [3 6] a n d all b a d ANLL (Table 11. W e p r e s e n t t h r e e a d d i t i o n a l cases a n d suggest t h a t t ( 1 6 : 2 1 ) ( p 1 1 . 2 : q 2 2 ) w a r r a n t s r e c o g n i t i o n as a n o t h e r p r i m a r y r e a r r a n g e m e n t in m y e l o i d l e u k e m i a . All t h r e e c a s e s h a d a c o m p l e t e r e m i s s i o n f o l l o w i n g c h e m o t h e r a p y . H o w e v e r , at least ()he p a t i e n t s u r v i v e d less t h a n a y e a r f o l l o w i n g r e m i s s i o n . CASE H I S T O R I E S
Case 1 A 2 1 - y e a r - o l d C h i n e s e m a l e p r e s e n t e d in J a n u a r y 1989 w i t h p e t e c h i a e . T h e h e m a t o logic f i n d i n g s at p r e s e n t a t i o n are s h o w n in T a b l e 2. After RBC a n d p l a t e l e t t r a n s f u s i o n s , l a b o r a t o r y d a t a i n c l u d e d a W B C of 2.1 × lO:~/mm :~, Hb 9.1 g/dl, M C V 97 fl, a n d From the Cancer Center of Southwest Biomedical Research Institute and Genetrix, In(:. [R. M.. C. B. R., A. M.. A. A. S.), Scottsdale, Arizona: LICSF Medical Center. lh~matoh~gyClinic (C. A. R.), San Francisco, California; Maricopa Medical Center (C. 11. ].). Phoenix. Ariznna: and University of Utah Medical Ccnh~r. Primary Children's Medical (;enter (R. S. L.). Salt l,ake City, l.ltah. Address reprint requests to: Dr. A. A. Sandberg, The Cancer Center oj Southwest Biomedical Research Institute and Genetrix, Inc.. 6401 E. Thomas Road. Scottsdale, Arizona 85251. Received July 16, 1990: accepted August 24, 1990.
83 ¢~ 1991 Elsevier Science Publishing Co., lnc, 655 Avenue of the Americas, New York, NY 10010
Cancer Genet Cytogenet 53:83 90 (1991) 0165-4608/91/$03.51)
84
R. Morgan et al.
Table 1
Karyotype of published cases with a t(16;21)(p11.2;q22.3)
Patient
Karyotype
No. cells
1 .(~
46,XY 46,XY,t(16;21)(pl 1.2;q22.3) 46,XX,del(9)(q12q22),t(16;21)(p11.2;q22.3) 47,XX,del(9)(q12q22),t(16;21)(p11.2q:22.3), + 10 46,XY 45,XY,- 2, + der(2)t(1;2)(q25;q33), - 16,- 21, + der(21)t(16;21)(pll.2:q22) 45,XY,- 2, + der(2)t(1:2)(q25;q33),t(4:6)(p14;q11), del(15)(q11.2q15), 16, 21.+der(21)t(16;21)(pll.2;q22) 46,XY,ins(7;2)(q11;p14p23),t(16;21)(p11;q22) 46,XY,t(16;21 )(pl 1:q22) 46,XY,t(16;21)(p11;q22)/45,XY,- 9,t(16:21)(p11;q22) 46,XX,t(16;21)(p11:q22)/47,XX,t(16;21)(p11;q22), + 10 46,XY,t(16;21}(p12-pl 3;q22] t(16;21)(p11;q22),t(3;11)(q29;p11), 6, + der{6)t(1 ;6)(q23;p25) t(16;21)(pl 1;q22)/t( 16;21)(p 11 ;q22),t(13;18)
1 14 6 9 1 2
2.~ 3.¢~
'~ P a l i e n t is d i s c u s s e d ~' N u m b e r
Reference
12 36 6 13 27 8 -- h h
141 141 161 13l 15] 15l
in l h i s r e p o r t .
of c e i l s w a s n o t a v a i l a b l e .
platelets 100 × 10:Umm:L A bone marrow aspirate showed normoblastic erythroid hypoplasia, granulocytic hypoplasia and decreased megakaryocytes, and 70% blasts with a reversed nuclear/cytoplasmic ratio, prominent nucleoli, and agranular cytoplasm. Some blasts showed erythrophagocytosis. The bone marrow biopsy showed 80% cellularity, 70% abnormal cells, normoblastic erythroid hypoplasia, and decreased megakaryocytes. The blasts had a large amount of cytoplasm with prominent granules and were peroxidase, chloroacetate esterase (CAE) and butyrate esterase negative. The III A stain for megakaryocytes was strongly positive ( + ) and the (:ell surface markers LN3, Leu4, and Leu M-1 were all negative. Based on the strong positivity of the megakaryocyte marker, Anti III A, the diagnosis of acute megakaryocytic leukemia (FAB classification M7) was established. The peroxidase, CAE, and butyrate esterase stains of the patient's blast cells were all negative, thereby excluding all other subgroups of AML, specifically M4. T- and B-cell markers were also negative. The patient was treated with high-dose cytarabine and mitoxantrone and remained in complete remission for 3 months during which time his bone marrow was harvested with plans for an autologous bone marrow transplant. The patient relapsed at 5 months and was reinducted witb high-dose etoposide and high-dose cytarabine. An autologous bone marrow transplant was performed after a second complete remission. The patient then relapsed again and died one year after presentation.
Case 2
A 33-year-old white female reported cramping abdominal pain, vomiting, easy bruisability, bleeding gums, and weakness for the previous 2 months. On the day of admission she suffered a syncopal episode. At initial presentation, she was hypotensive with a nonpalpable pnlse. Vital signs stabilized with administration of IV fluids and packed red blood cells. Examination disclosed a thin female in marked distress. Pertinent findings included hypoactive bowel sounds and a firm and diffusely tender abdomen. The stool was brown but positive for occult blood. Gums showed no hypertrophy or bleeding,
2
11.5 12.4 10.2
7.1 7.3
Hb
33.7
22
Hct
Hematological
97 114.5
MCV
findings
3.0 23.3 17.94 21.6 14.1 6.4
WBC
13
7
10
Ne 20 61 63 71 72 67
BI 10 52 188 70 72 22
P1 70 30 14 2 9 8
Ly
of all cases
Peripheral blood
at presentation
1
0 8
Met
involving
1
0
Eos 0 0 12 16 9 3
Mo 80 90 55 + N
Cel 70 + 57 47 53.2 80 +
BI
a t(16;21)(p11.2;q22.3)
19.2 19.4
0
Mo
30
EMM
Bone marrow
8.2 2.4
