SHORT COMMUNICATIONS 5 q - Anomaly in Acute Lymphoblastic Leukemia Roland Berger, Maryvonne Le Coniat, and Josette Derr
ABSTRACT: We report two n e w cases of c o m m o n acute lymphoblastic leukemia (ALL) with 5q--. This abnormality, w h i c h is u n c o m m o n in ALL, was previously reported in 14 cases of ALL of various subtypes and appears to occur less frequently in c o m m o n ALL than in other types of ALL.
INTRODUCTION
The 5 q - anomaly has been extensively studied in myelodysplastic syndromes (MDS), secondary acute nonlymphocytic leukemia (ANLL) and acute leukemia (AL) [1-3]. This anomaly is less frequent in malignant lymphoid cell proliferations and was associated with other chromosomal changes of the lymphoid type in prolymphocytic leukemia and various types of lymphomas [4]. We now report two new cases of acute lymphoblastic leukemia (ALL) with 5 q - and review other ALLs with 5 q - reported in the literature. MATERIALS AND METHODS Patient 1
B.O. (CG4836), a 15-year-old girl, was admitted to the hospital in March 1986 for treatment of ALL without tumoral syndrome. Hematologic data were as follows. In peripheral blood, the white blood cell (WBC) count 8.8 x 109/L with 44% blast cells, hemoglobin 9.9 g/dl, platelets 84 x 109/L. Bone marrow (BM) contained 31% lymphoblasts. Immunophenotype study allowed classification of this ALL as common ALL. Complete remission was achieved by chemotherapy (protocol FRALLE 83) in 1 month, and the patient later was treated according to the same protocol until April 1989. An ovarian relapse, without BM involvement, occurred in October 1989 and a second complete remission was achieved 1 month later. Bone marrow transplantation was performed in February 1990. The patient was in complete remission in November 1991.
platelet count of 187 x 109/L. Bone marrow showed 93% lymphoblasts. Immunophenotype determination allowed classification of this ALL as L2 of B lineage (stage 3 according to Nadler). Complete remission was achieved by chemotherapy (protocol FRALLE 87) in 1 month, and the child was treated later according to the same protocol. He was still in complete remission in December 1989. Cytogenetic Studies
Chromosome studies were performed before any treatment on unstimulated blood cell cultures for 24 and 48 hours in patient I and on 24-hour BM cell culture in patient 2. After RHG banding, chromosomes were classified according to the International System for Human Cytogenetic Nomenclature (ISCN) [5].
RESULTS Patient 1
Unstimulated blood cell cultures performed at diagnosis for 24 and 48 hours showed 10 metaphases with a normal karyotype of 46,XX, and eight metaphases with 47,XX, + del(5)(q31q33) (Fig. 1). Patient 2
Nine metaphases from 24-hour BM cell culture had normal karyotype, 46,XY and 10 had an abnormal karyotype with 46,XY,t(1;12)(p13;q21),del(5)(q14),del(6)(q21), (Fig. 1).
DISCUSSION Patient 2
T.D. (CG5793), a 5-year-old boy, was admitted to the hospital for pains in muscles and joints. Physical examination showed slight splenomegaly and lymph node enlargement. Hematologic examination showed a WBC count of 19.3 x 109/L with 89% lymphoblasts, hemoglobin 9.3 g/dl, and a
From the Unit~ INSERM U 301 and SDI No. 15954 CNRS, Institut de G~n~tique Mol6culaire, Paris, France. Address reprint requests to: Dr. Roland Berger, U 301, Unit6 de G~n~tique Mol6culaire, 27 rue Juliette Dodu, 75010, Paris, France. Received December 30, 1992; accepted February 5, 1992.
We report two new cases of ALL of B-cell lineage with 5 q - detected at diagnosis: one with + 5 q - and the other associated with t(1;12). This abnormality is uncommonly in ALL (four patients in 273 consecutively studied until 1990 in our laboratory, i.e., 1.5%), because most of the 5 q chromosome anomalies have been described in refractory anemia, "de novo," and "secondary" acute nonlymphocytic leukemia and MDS [1-3]. Lymphoid disorders such as prolymphocytic leukemia, non-Hodgkin lymphoma, mycosis fungoides, and adult T-cell lymphoma may rarely have 5 q - , as recently reported [4]. We found 14 cases of ALL with 5 q - reported in the literature [6-18] (Table 1) 201
© 1992 Elsevier Science P u b l i s h i n g Co., Inc. 655 A v e n u e of the Americas, New York, NY 10010
Cancer Genet Cytogenet 6 1 : 2 0 1 - 2 0 3 (1992) 0165-4608/92/$05.00
202
R. Berger et el.
t 5
2 1
12
5
6
Figure 1 Partial R-banded karyotypes of patients 1 and 2 (italics). Case 1, + del(5)(q31q33/; case 2, t(1;12),5q-, 6 q - (described in text). Arrows show rearranged chromosomes.
and only three had 5 q - as a u n i q u e structural chromosome abnormality [12, 17, 18]. ALL subtypes were variable, and of the eight cases i m m u n o p h e n o t y p i c a l l y studied, four were T-cell ALL, three were ALL with myeloid features, and one was c o m m o n ALL, as were the two present cases. The 5q - a n o m a l y thus appears to be less frequent in common ALL than in other types of ALL. The 5 q - chromosome was observed at relapse and was not detected at diagnosis in at least two patients. Various additional chromosome changes have been reported, some resembling those observed in ALL such as 9 p - and 1 2 p - and others more atypical for ALL such as 1 7 p - observed in two patients and in one with i(17q). Chromosome breakpoints on chro-
Table 1
mosome 5 are variable, and there is no clear difference between their localization in ALL and that in other blood disorders. The genes lost by the deletion of the long arm of chromosome 5 in ALL which could play a role in the malignant process have not yet been identified, and future investigations will determine whether they are the same as those implicated in n o n l y m p h o i d disorders.
REFERENCES
1. Van Den Berghe H, Vermaelen K, Mecucci C, Barbieri D, Tricot G (1985): The 5q anomaly. Cancer Genet Cytogenet 17:189-255.
Cases of 14 ALL with 5 q - reported in the literature
Sex/Age (yr)
Type of ALL
F/? M/4
ALL T-cell ALL
M/13 M/6
ALL ALL
F/72
ALL (with myeloid marker expression) ALL (with myeloid marker expression[ ALL ALL T-cell ALL, L2 T-Cell ALL, L1 ALL, L1
M/6 M/2 yr 6 mo F/IO yr 10 m F/25 M/25 M/7
Time of study
Abnormal karyotypes
Reference
Relapse Subsequent to lymphoma (?), untreated Diagnosis Diagnosis Remission Relapse Diagnosis
45,X, - X,dup(1}(q3lq41},del(5)(q22),del(17}(p11) 46,XY,del(5)(q12q23],del(9)(p21)
[6] [7, 8]
46-47, XY,del(5)(q15), + 8,del(12)(p12),del(17)(p11) 47,XY,del(5)(q13),del(15)(q15), +mar 46,XY,de](7)(q32) 46,XY,del(6/(q21)/47,idem, + 11/46,idem,- 15 46,XX,t(1;17)(p13;p36;p13),del(5)(q13q33),t(15;21)(q12,q22)
[9] [101
Relapse
63,XXY,dup(1)(qllq25},del(5)(q21), (cx)
[11l
Diagnosis Relapse Diagnosis Diagnosis Relapse
46,XY,del(5)(q15q31) 46,XX,del(5)(q15q31), + 17,i(17q), - 20 46,XX,del(1)(p33),del(5)(q13),del(11)(q13) 46,XY,del(5)(q12q31),del(12p11) 46,XY,del(1)(q23),del(5)(q23q31) del(6)(q21q25),
l 12] [121 [13] [14] [15]
Diagnosis Relapse Diagnosis
46,XY,de](5)(q15),t(9;22)(q34;q11) 46,XY,de](5)(q13q33) 92,XXYY,del(5)(q13q34)
[11]
der(10 )t(10; ?)(p15 ;?) / 46,i d e m , d u p ( 2q) / others
M/58 M/5 M/78
T-Cell ALL Common ALL, L1 ALL, L2 with myeloid features
Abbreviation: ALL,acute lymphoblasticleukemia.
[16] 117] [181
5q-
in ALL
2. Sandberg AA (1990): The Chromosomes in Human Cancer and Leukemia, 2nd ed., Elsevier, New York. 3. Pedersen B, Jensen IM (1991): Clinical and prognostic implications of chromosome 5q deletions: 96 high resolution studied patients. Leukemia 5:566-573. 4. Kerim S, Mecucci C, Cuneo A, Vandenberghe E, Louwagie A, Stul M, Michaux JL, Van Den Berghe H (1990): 5 q - anomaly in lymphoid disorders. Leukemia 4:12-15. 5. ISCN (1985): An International System for Human Cytogenetic Nomenclature. Harnden DG and Klinger HP (eds); published in collaboration with Cytogenet Cell Genet, Karger, Basel, 1985; also in Birth Defects: Original Article Series, Vol. 21, No. 1, (March of Dimes Birth Defects Foundation, New York, 1985). 6. Humbert JR, Morse HG, Hutter JJ, Rose B, Robinson A (1978): Nonleukemic dividing ceils in the blood of leukemic patients. Am J Hematol 4:217-224. 7. Abe S, Kohno S, Kubonoshi I, Minowada J, Sandberg AA (1979): Chromosomes and causation of human cancer and leukemia. XXXIII. 5q-- in a case of acute lymphoblastic leukemia (ALL). Am J Hematol 6:259-266. 8. Kowalczyk J, Sandberg AA (1983): A possible subgroup of ALL with 9 p - . Cancer Genet Cytogenet 9:383-385. 9. Prigogina EL, Fleischman EW, Puchkova GP, Kulagina OE, Majakova SA, Balakirev SA, Frenkel MA, Khvatova NV, Peterson IS (1979): Chromosomes in acute leukemia. Hum Genet 53:5-16. 10. Secker-Walker LM, Swansbury GJ, Lawler SD, Hardisty RM
203
11.
12.
13.
14.
15.
16.
17.
18.
(1979): Bone marrow chromosomes in acute lymphoblastic leukemia: A long term study. Med Pediatr Oncol 7:371-385. Haas OA, Bettelheim P, Scmidmeyer W, Gadner H, Ludwig H, Madjic O, Schulz U, (1985); 5 p - chromosome in acute leukemia with lymphoid morphology and myeloid membrane determinants. Blood 65:1342-1348. Kowalczyk JR, Grossi M, Sandberg AA (1985): Cytogenetic findings in childhood acute lymphoblastic leukemia. Cancer Genet Cytogenet 15:47-64. Berger R, Le Coniat M, Derr~ J, Vecchione D, Chen SJ (1989): Chromosomal rearrangement on chromosome 11q14-q21 in T cell acute leukemia. Leukemia 3:560-562. Berger R, Le Coniat M, Vecchione D, Derr~ J, Chen SJ (1990): Cytogenetic studies on 44 T-cell acute lymphoblastic leukerajas. Cancer Genet Cytogenet 44:69-75. Shikano T, Ishikawa Y, Ohkawa M, Hatayama Y, Nakadate H, Hatae Y, Takeda T (1990): Karyotypic changes from initial diagnosis to relapse in childhood acute leukemia. Leukemia 4:419-422. Takeuchi M, Ohnishi A, Tanaka K, Kimura N, Kamada N (1990): Acute T-lymphocytic leukemia with Ph 1and 5 q - chromosome abnormalities and rearrangements of bcr and TCR-8 genes. Leuk Res 14;885-893. Palau F, Prieto F, Badia L, Beneyto M, Benet I (1991): Chromosome 5 abnormalities in acute lymphoblastic leukemia. Cancer Genet Cytogenet 52:173-179. Valtat C, Uettwiller F, Flori E, Valtat B, Ruch JV, Oberling F (1991): Mosaic 46,XY/92,XXYY,del(5)(q13q34) in an adult lymphoblastic leukemia. Leukemia Res 15:651-653.
ABSTRACT: We report two n e w cases of c o m m o n acute lymphoblastic leukemia (ALL) with 5q--. This abnormality, w h i c h is u n c o m m o n in ALL, was previously reported in 14 cases of ALL of various subtypes and appears to occur less frequently in c o m m o n ALL than in other types of ALL.
INTRODUCTION
The 5 q - anomaly has been extensively studied in myelodysplastic syndromes (MDS), secondary acute nonlymphocytic leukemia (ANLL) and acute leukemia (AL) [1-3]. This anomaly is less frequent in malignant lymphoid cell proliferations and was associated with other chromosomal changes of the lymphoid type in prolymphocytic leukemia and various types of lymphomas [4]. We now report two new cases of acute lymphoblastic leukemia (ALL) with 5 q - and review other ALLs with 5 q - reported in the literature. MATERIALS AND METHODS Patient 1
B.O. (CG4836), a 15-year-old girl, was admitted to the hospital in March 1986 for treatment of ALL without tumoral syndrome. Hematologic data were as follows. In peripheral blood, the white blood cell (WBC) count 8.8 x 109/L with 44% blast cells, hemoglobin 9.9 g/dl, platelets 84 x 109/L. Bone marrow (BM) contained 31% lymphoblasts. Immunophenotype study allowed classification of this ALL as common ALL. Complete remission was achieved by chemotherapy (protocol FRALLE 83) in 1 month, and the patient later was treated according to the same protocol until April 1989. An ovarian relapse, without BM involvement, occurred in October 1989 and a second complete remission was achieved 1 month later. Bone marrow transplantation was performed in February 1990. The patient was in complete remission in November 1991.
platelet count of 187 x 109/L. Bone marrow showed 93% lymphoblasts. Immunophenotype determination allowed classification of this ALL as L2 of B lineage (stage 3 according to Nadler). Complete remission was achieved by chemotherapy (protocol FRALLE 87) in 1 month, and the child was treated later according to the same protocol. He was still in complete remission in December 1989. Cytogenetic Studies
Chromosome studies were performed before any treatment on unstimulated blood cell cultures for 24 and 48 hours in patient I and on 24-hour BM cell culture in patient 2. After RHG banding, chromosomes were classified according to the International System for Human Cytogenetic Nomenclature (ISCN) [5].
RESULTS Patient 1
Unstimulated blood cell cultures performed at diagnosis for 24 and 48 hours showed 10 metaphases with a normal karyotype of 46,XX, and eight metaphases with 47,XX, + del(5)(q31q33) (Fig. 1). Patient 2
Nine metaphases from 24-hour BM cell culture had normal karyotype, 46,XY and 10 had an abnormal karyotype with 46,XY,t(1;12)(p13;q21),del(5)(q14),del(6)(q21), (Fig. 1).
DISCUSSION Patient 2
T.D. (CG5793), a 5-year-old boy, was admitted to the hospital for pains in muscles and joints. Physical examination showed slight splenomegaly and lymph node enlargement. Hematologic examination showed a WBC count of 19.3 x 109/L with 89% lymphoblasts, hemoglobin 9.3 g/dl, and a
From the Unit~ INSERM U 301 and SDI No. 15954 CNRS, Institut de G~n~tique Mol6culaire, Paris, France. Address reprint requests to: Dr. Roland Berger, U 301, Unit6 de G~n~tique Mol6culaire, 27 rue Juliette Dodu, 75010, Paris, France. Received December 30, 1992; accepted February 5, 1992.
We report two new cases of ALL of B-cell lineage with 5 q - detected at diagnosis: one with + 5 q - and the other associated with t(1;12). This abnormality is uncommonly in ALL (four patients in 273 consecutively studied until 1990 in our laboratory, i.e., 1.5%), because most of the 5 q chromosome anomalies have been described in refractory anemia, "de novo," and "secondary" acute nonlymphocytic leukemia and MDS [1-3]. Lymphoid disorders such as prolymphocytic leukemia, non-Hodgkin lymphoma, mycosis fungoides, and adult T-cell lymphoma may rarely have 5 q - , as recently reported [4]. We found 14 cases of ALL with 5 q - reported in the literature [6-18] (Table 1) 201
© 1992 Elsevier Science P u b l i s h i n g Co., Inc. 655 A v e n u e of the Americas, New York, NY 10010
Cancer Genet Cytogenet 6 1 : 2 0 1 - 2 0 3 (1992) 0165-4608/92/$05.00
202
R. Berger et el.
t 5
2 1
12
5
6
Figure 1 Partial R-banded karyotypes of patients 1 and 2 (italics). Case 1, + del(5)(q31q33/; case 2, t(1;12),5q-, 6 q - (described in text). Arrows show rearranged chromosomes.
and only three had 5 q - as a u n i q u e structural chromosome abnormality [12, 17, 18]. ALL subtypes were variable, and of the eight cases i m m u n o p h e n o t y p i c a l l y studied, four were T-cell ALL, three were ALL with myeloid features, and one was c o m m o n ALL, as were the two present cases. The 5q - a n o m a l y thus appears to be less frequent in common ALL than in other types of ALL. The 5 q - chromosome was observed at relapse and was not detected at diagnosis in at least two patients. Various additional chromosome changes have been reported, some resembling those observed in ALL such as 9 p - and 1 2 p - and others more atypical for ALL such as 1 7 p - observed in two patients and in one with i(17q). Chromosome breakpoints on chro-
Table 1
mosome 5 are variable, and there is no clear difference between their localization in ALL and that in other blood disorders. The genes lost by the deletion of the long arm of chromosome 5 in ALL which could play a role in the malignant process have not yet been identified, and future investigations will determine whether they are the same as those implicated in n o n l y m p h o i d disorders.
REFERENCES
1. Van Den Berghe H, Vermaelen K, Mecucci C, Barbieri D, Tricot G (1985): The 5q anomaly. Cancer Genet Cytogenet 17:189-255.
Cases of 14 ALL with 5 q - reported in the literature
Sex/Age (yr)
Type of ALL
F/? M/4
ALL T-cell ALL
M/13 M/6
ALL ALL
F/72
ALL (with myeloid marker expression) ALL (with myeloid marker expression[ ALL ALL T-cell ALL, L2 T-Cell ALL, L1 ALL, L1
M/6 M/2 yr 6 mo F/IO yr 10 m F/25 M/25 M/7
Time of study
Abnormal karyotypes
Reference
Relapse Subsequent to lymphoma (?), untreated Diagnosis Diagnosis Remission Relapse Diagnosis
45,X, - X,dup(1}(q3lq41},del(5)(q22),del(17}(p11) 46,XY,del(5)(q12q23],del(9)(p21)
[6] [7, 8]
46-47, XY,del(5)(q15), + 8,del(12)(p12),del(17)(p11) 47,XY,del(5)(q13),del(15)(q15), +mar 46,XY,de](7)(q32) 46,XY,del(6/(q21)/47,idem, + 11/46,idem,- 15 46,XX,t(1;17)(p13;p36;p13),del(5)(q13q33),t(15;21)(q12,q22)
[9] [101
Relapse
63,XXY,dup(1)(qllq25},del(5)(q21), (cx)
[11l
Diagnosis Relapse Diagnosis Diagnosis Relapse
46,XY,del(5)(q15q31) 46,XX,del(5)(q15q31), + 17,i(17q), - 20 46,XX,del(1)(p33),del(5)(q13),del(11)(q13) 46,XY,del(5)(q12q31),del(12p11) 46,XY,del(1)(q23),del(5)(q23q31) del(6)(q21q25),
l 12] [121 [13] [14] [15]
Diagnosis Relapse Diagnosis
46,XY,de](5)(q15),t(9;22)(q34;q11) 46,XY,de](5)(q13q33) 92,XXYY,del(5)(q13q34)
[11]
der(10 )t(10; ?)(p15 ;?) / 46,i d e m , d u p ( 2q) / others
M/58 M/5 M/78
T-Cell ALL Common ALL, L1 ALL, L2 with myeloid features
Abbreviation: ALL,acute lymphoblasticleukemia.
[16] 117] [181
5q-
in ALL
2. Sandberg AA (1990): The Chromosomes in Human Cancer and Leukemia, 2nd ed., Elsevier, New York. 3. Pedersen B, Jensen IM (1991): Clinical and prognostic implications of chromosome 5q deletions: 96 high resolution studied patients. Leukemia 5:566-573. 4. Kerim S, Mecucci C, Cuneo A, Vandenberghe E, Louwagie A, Stul M, Michaux JL, Van Den Berghe H (1990): 5 q - anomaly in lymphoid disorders. Leukemia 4:12-15. 5. ISCN (1985): An International System for Human Cytogenetic Nomenclature. Harnden DG and Klinger HP (eds); published in collaboration with Cytogenet Cell Genet, Karger, Basel, 1985; also in Birth Defects: Original Article Series, Vol. 21, No. 1, (March of Dimes Birth Defects Foundation, New York, 1985). 6. Humbert JR, Morse HG, Hutter JJ, Rose B, Robinson A (1978): Nonleukemic dividing ceils in the blood of leukemic patients. Am J Hematol 4:217-224. 7. Abe S, Kohno S, Kubonoshi I, Minowada J, Sandberg AA (1979): Chromosomes and causation of human cancer and leukemia. XXXIII. 5q-- in a case of acute lymphoblastic leukemia (ALL). Am J Hematol 6:259-266. 8. Kowalczyk J, Sandberg AA (1983): A possible subgroup of ALL with 9 p - . Cancer Genet Cytogenet 9:383-385. 9. Prigogina EL, Fleischman EW, Puchkova GP, Kulagina OE, Majakova SA, Balakirev SA, Frenkel MA, Khvatova NV, Peterson IS (1979): Chromosomes in acute leukemia. Hum Genet 53:5-16. 10. Secker-Walker LM, Swansbury GJ, Lawler SD, Hardisty RM
203
11.
12.
13.
14.
15.
16.
17.
18.
(1979): Bone marrow chromosomes in acute lymphoblastic leukemia: A long term study. Med Pediatr Oncol 7:371-385. Haas OA, Bettelheim P, Scmidmeyer W, Gadner H, Ludwig H, Madjic O, Schulz U, (1985); 5 p - chromosome in acute leukemia with lymphoid morphology and myeloid membrane determinants. Blood 65:1342-1348. Kowalczyk JR, Grossi M, Sandberg AA (1985): Cytogenetic findings in childhood acute lymphoblastic leukemia. Cancer Genet Cytogenet 15:47-64. Berger R, Le Coniat M, Derr~ J, Vecchione D, Chen SJ (1989): Chromosomal rearrangement on chromosome 11q14-q21 in T cell acute leukemia. Leukemia 3:560-562. Berger R, Le Coniat M, Vecchione D, Derr~ J, Chen SJ (1990): Cytogenetic studies on 44 T-cell acute lymphoblastic leukerajas. Cancer Genet Cytogenet 44:69-75. Shikano T, Ishikawa Y, Ohkawa M, Hatayama Y, Nakadate H, Hatae Y, Takeda T (1990): Karyotypic changes from initial diagnosis to relapse in childhood acute leukemia. Leukemia 4:419-422. Takeuchi M, Ohnishi A, Tanaka K, Kimura N, Kamada N (1990): Acute T-lymphocytic leukemia with Ph 1and 5 q - chromosome abnormalities and rearrangements of bcr and TCR-8 genes. Leuk Res 14;885-893. Palau F, Prieto F, Badia L, Beneyto M, Benet I (1991): Chromosome 5 abnormalities in acute lymphoblastic leukemia. Cancer Genet Cytogenet 52:173-179. Valtat C, Uettwiller F, Flori E, Valtat B, Ruch JV, Oberling F (1991): Mosaic 46,XY/92,XXYY,del(5)(q13q34) in an adult lymphoblastic leukemia. Leukemia Res 15:651-653.
