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Translocation t(3;5)(q24;q32) in two acute nonlymphocytic leukemias
Translocation t(3;5)(q24;q32) in Two Acute Nonlymphocytic Leukemias Roland Berger, Alain Bernheim, Marie-Th6r~se Daniel, and Georges Flandrin
ABSTRACT: A translocation t(3;5)(q24;q32) has been detected in two patients with acute nonlymphocytic leukemia (ANLL), one with M2 and the other with M5. This translocatiun may be a new example of a nonrandom chromosome change in ANLL.
INTRODUCTION A large number of specific chromosomal changes have been described in malignant proliferations in the past years [1]. Some of them such as t(9;22)(q34;q11) and t(8;14)(q24;q32) were related with structural gene rearrangements or abnormal gene regulation. We report here an identical translocation detected in two children with different cytologic types of acute nonlymphocytic leukemia (ANLL). CASE REPORT
Case 1
N.T., CG 1660, a 7-year-old girl, was hospitalized in March 1980 for pallor and multiple cutaneous hematomas. The peripheral blood cell count showed 23 x 1 0 9 / L leukocytes with 66% myelobasts, 6% myelocytes, 3% metamyelocytes, 6% polymorphonulcear neutrophils, 16% eosinophils, 1% erythroblasts, and 2% lymphocytes, 80 x 109/L platelets, hemoglobin was 7.9 g/1O0 ml. The bone marrow was invaded by 62% blast cells, and few megakaryocytes were present. The diagnosis of acute myeloblastic leukemia, M2 according to the FAB nomenclature [2], was made. The blast cells, which had few azurophilic granules, had frequent small Auer rods, usually one ta three per cell. Peroxidase reaction was positive and nonspecific esterase was faintly positive without inhibition by sodium fluoride. Slight morphologic abnormalities were seen in both erythroblastic and neutrophilic cell lines. Megakaryocytes were nearly absent. Treatment with cytosine-arabinoside, rubidazone (daunorubicin benzoyl-hydrazone) and mitoguazone [methyl glyoxal bis(guanyl hydrazone) dichlohydrate], was started. No complete remission could be achieved and the patient died in July 1980. From the Laboratoire d'Oncologie et d'lmmunoh~matologie (R. B., A. B.), Unit~ INSERM U 301 (R. B., A. B., M-T. D., G. F.), and Laboratoire Central d'H~matologie, Hopital Saint-Louis (M-T. D., G. F.), Paris, France.
Address requests f o r reprints ta Dr. R. Berger, Laboratoire de Cytog6n~tique, C e n t r e Hayem, Hopital Saint-Louis, 1 Av. Claude Vellefaux, 75475 Paris Cedex 10, France.
261 © 1987 Elsevier Science Publishing Co., Inc. 52 Vanderbilt Ave., New York, NY 10017
Cancer Genet Cytogenet 28:261-265 (1987) 0165-4608/87/$03.50
262
1~. Berge.r e[ al.
Case 2
D.C., CG2687, a 16-year-old boy was hospitalized in April 1982. The diagnosis of monoblastic leukemia (M5 b) was made because the bone marrow was invaded by more than 90% blast cells, among them more than 80% were monoblasts and promonocytes. In addition to this monocytic component, some myeloblasts and maturing neutrophilic cells were present. These neutrophilic cells showed a partial but important myeloperoxidase deficiency, with a mixture of strongly positive, partially positive, and completely negative cells. The reaction with chloroacetate esterase showed a similar partial deficiency in the neutrophilic cells. The monocytic nature of the large blast was confirmed by their strong positivity for nonspecific esterase (naphtol ASD acetate) and inhibition of this reaction by sodium fluoride. On bone marrow smears, erythroblasts were very rare. By contrast, megakaryocytes were very abundanl, far more than in a n o r l n a l bone marrow, h n m a t u r e and mature forms were present, bypodiploid (:ells were rare and large (:ells with usual nuclear features predominated. The peripheral blood cell count showed 69 × 10~/L leukocytes with 41% blast cells, 1% myelocytes, 1% p o l y m o r p h o n u c l e a r neutrophils, 25% monocytes, and 9% lymphocytes. The platelet count was 415 × 10~'/L and the hemoglobin 10.3 g/100 ml. The child was treated according to the AM 081 protocol [31 and complete remission was achieved 1 m o n t h later. The treatment was followed until April 1985. Since that time the child remains in good health and in complete remission.
CYTOGENETICS
Chromosome studies were performed on 48-hour cultured bone marrow and on u n s t i m u l a t e d blood cell cultures for 48 hours and 72 hours in the first case, 24 and 48 hours in the second. Phytohemagglutinin (PHA) stimulated blood (:ell culture for 72 hours was also performed on the cells of both patients. (;-banding using trypsin (GTG), and R-banding after heating (RHG) were performed {4].
Case 1
Only three metaphases could be analysed in the bone marrow culture. The karyotype was abnormal, 46,XX,t(3;5)(q24;q32) in the three cells. The same abnormality (Fig. 1) was observed in the blood cell culture (65 metaphase) and a normal karyotype was observed in one single cell. In the PHA-stimulated blood culture, 12 me(aphases had the translocation and two were normal.
Case 2
All the examined metaphases, 25 in bone marrow, 27 in unstimulated blood cell cultures, had the same karyotype: 46,XY,t(3;5)(q24;q32), (Fig. 1). A PHA-stimulated blood culture for 72 hours was performed in remission (November 1982) and showed only a normal 46,XY karyotype.
DISCUSSION
The same translocation t(3;5)(q24;q32) was detected in two children with ANLL. However, the subtypes were different, one was M2 and the other M5. In addition careful examination of both cases did not show any c o m m o n features. Case 1 (M2)
263
t(3;5)(q24;q32) in ANLL
3
5 G
2
ii'
2ii Figure 1 Partial karyotypes showing the t(3;5) in patients 1 and 2, G, G-banding; R, R-banding. had only myeloblasts and slight neutrophilic and erythroblastic abnormalities. Case 2 (M5b) had, in addition to the monocytic component, obvious abnormalities of the neutrophilic series with myeloperoxidase deficiency and very unusual megakaryocytic hyperplasia. The outcome was also different, one child did not achieve a remission and the other is surviving in complete remission 4 years after the diagnosis. This translocation has been observed only rarely (two of 519 patients with primary ANLL) and few cases of t(3q;5q) have been previously reported [5-11] (Table 1). The breakpoints have differed and the cytologic types varied from one case to another. Rearrangements of chromosome #3, involving bands 3p21 and 3q26, have been
264 Table 1
R. Berger et al.
T r a n s l o c a t i o n s t(3q;5q) in A N L L ANLL type
Karyotype
[Ref.]
Acute myeloblastic leukemia Acute myelomonocytic leukemia Acute myeloblastic leukemia Erythroleukemia Acute myelomonocytic leukemia (exposed to insecticides) Acute myeloblastic leukemia (M1) Erythroleukemia
47,XY,t(3;5)(q21;q31),t(1 ;13)(p36;q14).-- 8, + 22 46,xY,t(3;5)(q25;q33?) 47,X,Xq-,t(3;5), 5,t(11;?),t(12;17),-18,-21,+6 mar 46,XY,t(3;5)(q13 ;q28) 44,xY,t(3;5)(qter;q13),t(7;12)(ql 2;q14),t(7;lo)(q12;q21), -8,-17,-18, 20 46,XY, 5,+der(5)t(3;5)(q25;qter) 46,XX,t(3;5)(q22;q35)
15] 16l 17] [8] [9] [10] [11 ]
a s s o c i a t e d w i t h m e g a k a r y o c y t i c a b n o r m a l i t i e s [12, 13]. The b r e a k p o i n t s in the t w o patients r e p o r t e d h e r e w e r e different, but one of t h e m had a h i g h p e r i p h e r a l p l a t e l e t count. B a n d 5q32 is i n v o l v e d in s o m e interstitial d e l e t i o n s of c h r o m o s o m e # 5 , d e s c r i b e d m a i n l y in the 5q- s y n d r o m e [14]. T h e i n t e r e s t of the t r a n s l o c a t i o n r e p o r t e d here is to suggest that a n e w n o n r a n d o m t(3;5)(q24;q32) m a y exist. The l o c a l i z a t i o n of genes c o d i n g for transferrin at 3q21-q26 [15] a n d GM-CSF at 5q21-q32 [16, 17] suggest that t h e s e genes h a v e to be i n v e s t i g a t e d in t h e s e t r a n s l o c a t i o n s .
REFERENCES 1. Berger R, Bloomfield CD, Sutherland GR (1985)'. Report of the committee on chromosome rearrangements in neoplasia and on fragile sites. Hnman Gene Mapping 8. Cytogenetic Cell Genet 40:490-535. 2. Bennet JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C (1976): Proposals for the classification of acute leukaemias: French-American-British (FAB) Co-operative group. Br J Haematol 33:451 458. 3. Marry M, Lepage E, Guy H, Bordessoule D, Desablens B, Harousseau JL, Guilhot F, Leverger G, Schaison G, Boiron M (1986): Remission induction and maintenance modalities in acute myeloid leukemia (AML): A multicentric randomized study. International Symposium on Acute Leukemia, Prognostic, and Treatment Strategies. Mtinster (in press). 4. ISCN (1978): An International System for Human Cytogenetic Nomenclature (1978). Birth Defects: Original Article Series, Vol. XIV, Nol 8 (The National Foundation, New York, 1978); also in Cytogenet Cell Genet 21:309-404 (1978). 5. Oshimura M, Hayata I, Kakati S, Sandberg AA (1976): Chromosomes and causation of human cancer and leukemia. XVII. Banding stndies in acute myeloblastic leukemia (AML). Cancer 38:748-761. 6. Rowley JD, Potter D (1976): Chromosomal banding patterns in acute nonlymphocytic leukemia. Blood 47:705-721. 7. Pedersen-Bjergaard J, Haahr S, Philip P, Thomsen M, Jensen G, Erboll J, Nissen NI (1980): Abolished production of interferon leukocyte of patients with the acquired cytogenetic abnormalities 5 q - or 5 in secondary and de novo acute nonlymphocytic leukaemia. Br J Haematol 46:211-233. 8. Hagemeijer A, H~ilhen K, Abels J (1981): Cytogenetic follow-up of patients with nonlymphocytic leukemia II. Acute nonlymphocytic leukemia. Cancer Genet Cytogenet 3:109124. 9. Mitelman F, Nilson PG, Brandt L, Alimena G, Montuoro A, Dallapicola B (1981): Chromosome pattern, occupation, and clinical features in patients with acute nonlymphocytic leukemia. Cancer Genet Cytogenet 4:197-214. 10. Yunis JJ (1984): Recurrent chromosomal defects are found in most patients with acute nonlymphocytic leukemia. Cancer Genet Cytogenet 11:125 137.
t(3;5)(q24;q32) i n A N L L
265
11. Mitelman F (1985): Catalog of Chromosome Aberration in Cancer, 2nd Ed. Alan R Liss, New York. 12. Sweet DL, Golomb HM, Rowley JD, Vardiman JM (1979): Acute myelogenous leukemia and thrombocytemia associated with an abnormality of chromosome 3. Cancer Genet Cytogenet 1:33-37. 13. Bernstein R, Pinto MR, Mendelow B (1982): Chromosome 3 abnormalities in acute nonlymhocytic leukemia (ANLL) with abnormal thrombopoiesis: Report of three patients with a " n e w " inversion anomaly and a further case of homologous translocation. Blood 60:613-617. 14. Van den Berghe H, Vermaelen K, Mecucci C, Barbieri D, Tricot G (1985): The 5 q - anomaly. Cancer Genet Cytogenet 17:189-255. 15. Kidd KK, Gusella J (1985): Report of the committee on the genetic constitution of chromosome 3 et 4. Human Gene Mapping 8. Cytogenetic Cell Genet 40:107-127. 16. Huebner K, Isobe M, Croce CM, Golde DW, Kaufman SE, Gasson JC (1985): The human gene encoding GM-CSF is at 5q21-q32, the chromosome region deleted in the 5 q - anomaly. Science 230:1282 1285. 17. Le Beau MM, Westbrook CA, Diaz MO, Larson RA, Rowley JD, Gasson JC, Golde DW, Sherr CJ (1986): Evidence for the involvement of GM-CSF and FMS in the deletion (5q) in myeloid disorders. Science 231:984-987.
ABSTRACT: A translocation t(3;5)(q24;q32) has been detected in two patients with acute nonlymphocytic leukemia (ANLL), one with M2 and the other with M5. This translocatiun may be a new example of a nonrandom chromosome change in ANLL.
INTRODUCTION A large number of specific chromosomal changes have been described in malignant proliferations in the past years [1]. Some of them such as t(9;22)(q34;q11) and t(8;14)(q24;q32) were related with structural gene rearrangements or abnormal gene regulation. We report here an identical translocation detected in two children with different cytologic types of acute nonlymphocytic leukemia (ANLL). CASE REPORT
Case 1
N.T., CG 1660, a 7-year-old girl, was hospitalized in March 1980 for pallor and multiple cutaneous hematomas. The peripheral blood cell count showed 23 x 1 0 9 / L leukocytes with 66% myelobasts, 6% myelocytes, 3% metamyelocytes, 6% polymorphonulcear neutrophils, 16% eosinophils, 1% erythroblasts, and 2% lymphocytes, 80 x 109/L platelets, hemoglobin was 7.9 g/1O0 ml. The bone marrow was invaded by 62% blast cells, and few megakaryocytes were present. The diagnosis of acute myeloblastic leukemia, M2 according to the FAB nomenclature [2], was made. The blast cells, which had few azurophilic granules, had frequent small Auer rods, usually one ta three per cell. Peroxidase reaction was positive and nonspecific esterase was faintly positive without inhibition by sodium fluoride. Slight morphologic abnormalities were seen in both erythroblastic and neutrophilic cell lines. Megakaryocytes were nearly absent. Treatment with cytosine-arabinoside, rubidazone (daunorubicin benzoyl-hydrazone) and mitoguazone [methyl glyoxal bis(guanyl hydrazone) dichlohydrate], was started. No complete remission could be achieved and the patient died in July 1980. From the Laboratoire d'Oncologie et d'lmmunoh~matologie (R. B., A. B.), Unit~ INSERM U 301 (R. B., A. B., M-T. D., G. F.), and Laboratoire Central d'H~matologie, Hopital Saint-Louis (M-T. D., G. F.), Paris, France.
Address requests f o r reprints ta Dr. R. Berger, Laboratoire de Cytog6n~tique, C e n t r e Hayem, Hopital Saint-Louis, 1 Av. Claude Vellefaux, 75475 Paris Cedex 10, France.
261 © 1987 Elsevier Science Publishing Co., Inc. 52 Vanderbilt Ave., New York, NY 10017
Cancer Genet Cytogenet 28:261-265 (1987) 0165-4608/87/$03.50
262
1~. Berge.r e[ al.
Case 2
D.C., CG2687, a 16-year-old boy was hospitalized in April 1982. The diagnosis of monoblastic leukemia (M5 b) was made because the bone marrow was invaded by more than 90% blast cells, among them more than 80% were monoblasts and promonocytes. In addition to this monocytic component, some myeloblasts and maturing neutrophilic cells were present. These neutrophilic cells showed a partial but important myeloperoxidase deficiency, with a mixture of strongly positive, partially positive, and completely negative cells. The reaction with chloroacetate esterase showed a similar partial deficiency in the neutrophilic cells. The monocytic nature of the large blast was confirmed by their strong positivity for nonspecific esterase (naphtol ASD acetate) and inhibition of this reaction by sodium fluoride. On bone marrow smears, erythroblasts were very rare. By contrast, megakaryocytes were very abundanl, far more than in a n o r l n a l bone marrow, h n m a t u r e and mature forms were present, bypodiploid (:ells were rare and large (:ells with usual nuclear features predominated. The peripheral blood cell count showed 69 × 10~/L leukocytes with 41% blast cells, 1% myelocytes, 1% p o l y m o r p h o n u c l e a r neutrophils, 25% monocytes, and 9% lymphocytes. The platelet count was 415 × 10~'/L and the hemoglobin 10.3 g/100 ml. The child was treated according to the AM 081 protocol [31 and complete remission was achieved 1 m o n t h later. The treatment was followed until April 1985. Since that time the child remains in good health and in complete remission.
CYTOGENETICS
Chromosome studies were performed on 48-hour cultured bone marrow and on u n s t i m u l a t e d blood cell cultures for 48 hours and 72 hours in the first case, 24 and 48 hours in the second. Phytohemagglutinin (PHA) stimulated blood (:ell culture for 72 hours was also performed on the cells of both patients. (;-banding using trypsin (GTG), and R-banding after heating (RHG) were performed {4].
Case 1
Only three metaphases could be analysed in the bone marrow culture. The karyotype was abnormal, 46,XX,t(3;5)(q24;q32) in the three cells. The same abnormality (Fig. 1) was observed in the blood cell culture (65 metaphase) and a normal karyotype was observed in one single cell. In the PHA-stimulated blood culture, 12 me(aphases had the translocation and two were normal.
Case 2
All the examined metaphases, 25 in bone marrow, 27 in unstimulated blood cell cultures, had the same karyotype: 46,XY,t(3;5)(q24;q32), (Fig. 1). A PHA-stimulated blood culture for 72 hours was performed in remission (November 1982) and showed only a normal 46,XY karyotype.
DISCUSSION
The same translocation t(3;5)(q24;q32) was detected in two children with ANLL. However, the subtypes were different, one was M2 and the other M5. In addition careful examination of both cases did not show any c o m m o n features. Case 1 (M2)
263
t(3;5)(q24;q32) in ANLL
3
5 G
2
ii'
2ii Figure 1 Partial karyotypes showing the t(3;5) in patients 1 and 2, G, G-banding; R, R-banding. had only myeloblasts and slight neutrophilic and erythroblastic abnormalities. Case 2 (M5b) had, in addition to the monocytic component, obvious abnormalities of the neutrophilic series with myeloperoxidase deficiency and very unusual megakaryocytic hyperplasia. The outcome was also different, one child did not achieve a remission and the other is surviving in complete remission 4 years after the diagnosis. This translocation has been observed only rarely (two of 519 patients with primary ANLL) and few cases of t(3q;5q) have been previously reported [5-11] (Table 1). The breakpoints have differed and the cytologic types varied from one case to another. Rearrangements of chromosome #3, involving bands 3p21 and 3q26, have been
264 Table 1
R. Berger et al.
T r a n s l o c a t i o n s t(3q;5q) in A N L L ANLL type
Karyotype
[Ref.]
Acute myeloblastic leukemia Acute myelomonocytic leukemia Acute myeloblastic leukemia Erythroleukemia Acute myelomonocytic leukemia (exposed to insecticides) Acute myeloblastic leukemia (M1) Erythroleukemia
47,XY,t(3;5)(q21;q31),t(1 ;13)(p36;q14).-- 8, + 22 46,xY,t(3;5)(q25;q33?) 47,X,Xq-,t(3;5), 5,t(11;?),t(12;17),-18,-21,+6 mar 46,XY,t(3;5)(q13 ;q28) 44,xY,t(3;5)(qter;q13),t(7;12)(ql 2;q14),t(7;lo)(q12;q21), -8,-17,-18, 20 46,XY, 5,+der(5)t(3;5)(q25;qter) 46,XX,t(3;5)(q22;q35)
15] 16l 17] [8] [9] [10] [11 ]
a s s o c i a t e d w i t h m e g a k a r y o c y t i c a b n o r m a l i t i e s [12, 13]. The b r e a k p o i n t s in the t w o patients r e p o r t e d h e r e w e r e different, but one of t h e m had a h i g h p e r i p h e r a l p l a t e l e t count. B a n d 5q32 is i n v o l v e d in s o m e interstitial d e l e t i o n s of c h r o m o s o m e # 5 , d e s c r i b e d m a i n l y in the 5q- s y n d r o m e [14]. T h e i n t e r e s t of the t r a n s l o c a t i o n r e p o r t e d here is to suggest that a n e w n o n r a n d o m t(3;5)(q24;q32) m a y exist. The l o c a l i z a t i o n of genes c o d i n g for transferrin at 3q21-q26 [15] a n d GM-CSF at 5q21-q32 [16, 17] suggest that t h e s e genes h a v e to be i n v e s t i g a t e d in t h e s e t r a n s l o c a t i o n s .
REFERENCES 1. Berger R, Bloomfield CD, Sutherland GR (1985)'. Report of the committee on chromosome rearrangements in neoplasia and on fragile sites. Hnman Gene Mapping 8. Cytogenetic Cell Genet 40:490-535. 2. Bennet JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C (1976): Proposals for the classification of acute leukaemias: French-American-British (FAB) Co-operative group. Br J Haematol 33:451 458. 3. Marry M, Lepage E, Guy H, Bordessoule D, Desablens B, Harousseau JL, Guilhot F, Leverger G, Schaison G, Boiron M (1986): Remission induction and maintenance modalities in acute myeloid leukemia (AML): A multicentric randomized study. International Symposium on Acute Leukemia, Prognostic, and Treatment Strategies. Mtinster (in press). 4. ISCN (1978): An International System for Human Cytogenetic Nomenclature (1978). Birth Defects: Original Article Series, Vol. XIV, Nol 8 (The National Foundation, New York, 1978); also in Cytogenet Cell Genet 21:309-404 (1978). 5. Oshimura M, Hayata I, Kakati S, Sandberg AA (1976): Chromosomes and causation of human cancer and leukemia. XVII. Banding stndies in acute myeloblastic leukemia (AML). Cancer 38:748-761. 6. Rowley JD, Potter D (1976): Chromosomal banding patterns in acute nonlymphocytic leukemia. Blood 47:705-721. 7. Pedersen-Bjergaard J, Haahr S, Philip P, Thomsen M, Jensen G, Erboll J, Nissen NI (1980): Abolished production of interferon leukocyte of patients with the acquired cytogenetic abnormalities 5 q - or 5 in secondary and de novo acute nonlymphocytic leukaemia. Br J Haematol 46:211-233. 8. Hagemeijer A, H~ilhen K, Abels J (1981): Cytogenetic follow-up of patients with nonlymphocytic leukemia II. Acute nonlymphocytic leukemia. Cancer Genet Cytogenet 3:109124. 9. Mitelman F, Nilson PG, Brandt L, Alimena G, Montuoro A, Dallapicola B (1981): Chromosome pattern, occupation, and clinical features in patients with acute nonlymphocytic leukemia. Cancer Genet Cytogenet 4:197-214. 10. Yunis JJ (1984): Recurrent chromosomal defects are found in most patients with acute nonlymphocytic leukemia. Cancer Genet Cytogenet 11:125 137.
t(3;5)(q24;q32) i n A N L L
265
11. Mitelman F (1985): Catalog of Chromosome Aberration in Cancer, 2nd Ed. Alan R Liss, New York. 12. Sweet DL, Golomb HM, Rowley JD, Vardiman JM (1979): Acute myelogenous leukemia and thrombocytemia associated with an abnormality of chromosome 3. Cancer Genet Cytogenet 1:33-37. 13. Bernstein R, Pinto MR, Mendelow B (1982): Chromosome 3 abnormalities in acute nonlymhocytic leukemia (ANLL) with abnormal thrombopoiesis: Report of three patients with a " n e w " inversion anomaly and a further case of homologous translocation. Blood 60:613-617. 14. Van den Berghe H, Vermaelen K, Mecucci C, Barbieri D, Tricot G (1985): The 5 q - anomaly. Cancer Genet Cytogenet 17:189-255. 15. Kidd KK, Gusella J (1985): Report of the committee on the genetic constitution of chromosome 3 et 4. Human Gene Mapping 8. Cytogenetic Cell Genet 40:107-127. 16. Huebner K, Isobe M, Croce CM, Golde DW, Kaufman SE, Gasson JC (1985): The human gene encoding GM-CSF is at 5q21-q32, the chromosome region deleted in the 5 q - anomaly. Science 230:1282 1285. 17. Le Beau MM, Westbrook CA, Diaz MO, Larson RA, Rowley JD, Gasson JC, Golde DW, Sherr CJ (1986): Evidence for the involvement of GM-CSF and FMS in the deletion (5q) in myeloid disorders. Science 231:984-987.