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Trisomy 11 in a patient with Ph-negative chronic myelogenous leukemia
Trisomy 11 in a Patient with Ph-Negative Chronic Myelogenous Leukemia Toshiyuki Yamada, Motomichi Sasaki, and Tsugumichi Kawamura
ABSTRACT:
A case of Ph-negative chronic myelagenous leukemia associated with functional reduction of platelets is described. Bone marrow cells examined in the blastic phase showed a stem line karyotype of 47.XY, * 11.
INTRODUCTION To date; there are five cases of trisomy 11 reported as the sole a b n o r m a l i t y in hematopoietic disorders, i.e., three patients with acute n o n l y m p h o c y t i c leukemia (ANLL)-M1 or M2 [1-3], one with ANLL-M4 [4], and one with p r e l e u k e m i a [5]. We wish to report here a case of Ph-negative chronic myelogenous leukemia (CML) associated with trisomy 11 as the sole a b n o r m a r i t y in the bone marrow cells. CASE REPORT The patient (KN 949), a 78-year-old p h e n o t y p i c a l l y normal male, was first a d m i t t e d to the Takikawa M u n i c i p a l Hospital on August 19, 1981, c o m p l a i n i n g of chest pains while walking. He had a history of h y p e r t e n s i o n (1977) and diabetes (1980), and his second son died of acute myeloblastic leukemia (AML). Clinical examination revealed slightly anemic conjunctivae with no evidence of jaundice. The liver, spleen, and l y m p h nodes were not enlarged. The patient was suspected to have AML on the basis of available laboratory data, i n c l u d i n g a WBC count of 3.94 x 104/ m m a with 50% blast cells. He failed to r e s p o n d to chemotherapies, and was referred to the A s a h i k a w a M u n i c i p a l Hospital on November 18, 1981, for a precise diagnosis and further care. The hematologic data were as follows: WBC 5.38 x 104/mm 3 (leukemic cells, 79%); RBC 3.07 x 108/ram3; h e m o g l o b i n 9.4g/dl; hematocrit 28.8%; and platelets 3.71 × 105/mm 3. The bone marrow aspirate s h o w e d 7 x 104/mm 3 nucleated cells (leukemic cells, 74%) and 25/mm 3 megakaryocytes, without detectable erythroid cells. The leukemic cells were variable in size, showing decreased cytoplasm/nucleus ratio, and the b a s o p h i l i c c y t o p l a s m without granulation. The nucleus showed finely d i s p e r s e d chromatin and p r o m i n e n t nucleoli. The existence of the hiatus leukemicus indicated the poor maturation of the leukemic cells. The neutrophil alkaline p h o s p h a t a s e was found to be low (rate, 12%; score, 23), camFrom the Chromosome Research Unit, Faculty of Science, Hokkaido University, Sapporo (T.Y., M.S.), • and the Department of Internal Medicine. Asahikawa Municipal Hospital, Asahikawa (T.K.), Japan. Address requests for reprints to Dr. Motomichi Sasaki, Chromosome Research Unit, Faculty of Science, Hokkaido University, North 10, West 8, Sapporo 060, Japan. Received May 25, 1985; accepted August 19, 1985. 343 © 1986 Elsevier Science Publishing Co., Inc. 52 Vanderbilt Ave., New York. NY 10017
Cancer Genet Cytogenet 21:343-345(1986) 0165-4608/86/$03.50
344
T. Yamada, M. Sasaki, and T. Kawamura pared with the control value (rate, 97%: score 331), and platelet function tests revealed a marked decrease in the a d h e s i v e n e s s to glass beads as well as in the aggregation rate as measured with a d e n o s i n e d i p h o s p h a t e , suggesting the possible precedence of chronic phase. The leukemic cells showed negative reactions to peroxidase, periodic acid-Schiff, and esterase, la antigen [6], c o m m o n ALL antigen [7], surface Ig, and the monoclonal antibody, l,eu-1 [8] were all negative and no cells formed E-rosettes, suggesting that the leukemic cells were of nonlymphoid cell origin. The patient, thus, was diagnosed to be in the acute phase of CML. Combination therapies with vindesin plus L-asparaginase plus predonine, and aclarubicin plus behenoyl-ara C were unsuccessful. On April 14, 1982 (8 months after the first admission), the patient died of p n e u m o n i a .
CYTOGENETIC FINDINGS Chromosomal analysis was performed on short-term cultures of bone marrow cells, on November 20, 1981. Twenty metaphases were analyzed after Q-banding, among which 17 showed a 47.XY, + 11 karyotype (Fig. 1 ), while the remaining three variant cells showed a random loss ( - 7 , - 1 4 , or - 1 7 ) from the stem line karyotype probably due to artifacts. We did not examine the constitutional karyotype of this patient but, considering he had a normal phenotype, the trisomic cells were thought to be leukemic cells. DISCUSSION There have been no reported cases of CML with trisomy 11 as the sole abnormality. Although four of the five reported cases of blood disorders with trisomy 11 had karyotypically normal cells in the bone marrow samples, our case and one other Figure 1
Representative karyotype of a bone marrow (:ell with 47,XY,- 11.
Ph-Negatiw; CML
345
r e p o r t e d case 13] c o n t a i n e d (;xclusively t r i s o m i c 11 cells in the b o n e m a r r o w . It is u n k n o w n , h o w e v e r , if the t r i s o m i c cells w e r e f o r m e d in the stem cells, or a c q u i r e d d u r i n g m a l i g n a n t g r o w t h , or as a result of c h e m o t h e r a p i e s . It is i n t e r e s t i n g to note that P h - n e g a t i v e CML cases are g e n e r a l l y d i p l o i d w i t h o u t c h a r a c t e r i s t i c or consistent k a r y o t y p i c c h a n g e e x c e p t for the i n c i d e n t a l o c c u r r e n c e of t r i s o m y 8 and s o m e o t h e r less c o m m o n c h a n g e s i n c l u d i n g a m i s s i n g Y [9]. Recent reports point to occasional a s s o c i a t i o n of t h r o m b o c y t o p e n i a a n d / n r f u n c t i o n a l r e d u c t i o n of platelets with + 11 or 11q + [5, 10, 11 ]. O u r patient e x h i b i t e d a c o n s i d e r a b l e extent of functional r e d u c t i o n of platelets, in spite of the fact that the platelet c o u n t was h i g h e r than the n o r m a l value. F u r t h e r a c c u m u l a t i o n of data is n e e d e d to better u n d e r s t a n d the p a t h o g e n i c role of t r i s o m y 11 in v a r i o u s h e m a t o l o g i c disorders. W h e t h e r or not the h u m a n p r o t o o n c o g e n e c-Ha-ras 1, w h i c h is located on the short arm of t:hrc*m o s o m e #11 [12], is a m p l i f i e d in the t r i s o m i c 11 cells is a n o t h e r q u e s t i o n in need of a solution. Supported in par! by a Grant-in-Aid for Cancer Research from the Ministry of I':ducation, Science and Culture, Japan.
REFERENCES 1. Yunis JJ, Bloomfield CD, Ensrud K (1981): All patients with acute nonlymphocytic leukemia may have a chromosomal defect. N Engl J Med 16:135--139. 2. Fitzgerald PH, Morris CM. Fraser GJ, Giles LM, Hamer JW, Heaton DC, Beard MEJ (1983): Nonrandom cytogenetic changes in New Zealand patients with acute myeloid h;ukemia. Cam:er Genet Cytogenet 8:51-66. 3. Li YS, Khalid G, Hayhoe FGJ (1983): Correlation between chromosomal pattern, cytological subtypes, response to therapy, and survival in acute myeloid leukaemia. Scand J Haematol 30:265-277. 4. liagemeijer A, Hahlen K, Abels ] (1981J: Cytogenetic follow-up of patients with uonlymphocytic leukemia. II. Acute nonlymphocytic leukemia. Cancer Genet Cytogenet 3:109124. 5. Gangji 13, Noseda A, Wybran J, Verhest A {1985}: Trisomy 11 in preleukemia. Cancer Cenet Cytogenet 14:119- 123. 6. Billing R], Safani M, Peterson P (1976): Isolation and characterization of human B cell alloantigens. J lmmunol 117:1589- 1593. 7. Greaves MF. Brown (;, Rapson NT, Lister TA (1975): Antisera to acute lymphoblastic leukemia cells. Clin Immunol lmmunopathol 4:67-84. 8. Wang ('Y, Good RA, Ammirati P, Dymbort G, Evans RI, (1980): hlentificatiou of a p69,71 complex expressed on human T cells sharing determinants with B-type chronic: lymphatic: leukemic cells. J. Exp Med 151:1539-1544. 9. Kohno S, Abe S, Sandberg AA (1979]: The chromosomes and causation of human cancer and leukemia: XXXVIII. Cytogenetic experience in Phi-negative chronic myelocytic leukemia [CMI,). Am J Hemato] 7:281-291. 10. Tricot G, Griel A, Verwilghen RI, (1982): Thrombocytopenia as presenting symptom of preleukaemia in 3 patients. Stand J Haematol 28:243-250. 11. Tricot G, Van Den Berghe H (1982): Isolated peripheral thrombocytopenia as presenting symptom in preleukemia: A report of two cases with 11q+. Cancer Genet Cytogenet 5:147-151, 12. de Martinville B. Giacalone J, Shih C, Weinberg RA, Francke V (1983): Oncogene from human EJ bladder carcinoma is located on the short arm of chromosome 11. Science 219:498-501.
ABSTRACT:
A case of Ph-negative chronic myelagenous leukemia associated with functional reduction of platelets is described. Bone marrow cells examined in the blastic phase showed a stem line karyotype of 47.XY, * 11.
INTRODUCTION To date; there are five cases of trisomy 11 reported as the sole a b n o r m a l i t y in hematopoietic disorders, i.e., three patients with acute n o n l y m p h o c y t i c leukemia (ANLL)-M1 or M2 [1-3], one with ANLL-M4 [4], and one with p r e l e u k e m i a [5]. We wish to report here a case of Ph-negative chronic myelogenous leukemia (CML) associated with trisomy 11 as the sole a b n o r m a r i t y in the bone marrow cells. CASE REPORT The patient (KN 949), a 78-year-old p h e n o t y p i c a l l y normal male, was first a d m i t t e d to the Takikawa M u n i c i p a l Hospital on August 19, 1981, c o m p l a i n i n g of chest pains while walking. He had a history of h y p e r t e n s i o n (1977) and diabetes (1980), and his second son died of acute myeloblastic leukemia (AML). Clinical examination revealed slightly anemic conjunctivae with no evidence of jaundice. The liver, spleen, and l y m p h nodes were not enlarged. The patient was suspected to have AML on the basis of available laboratory data, i n c l u d i n g a WBC count of 3.94 x 104/ m m a with 50% blast cells. He failed to r e s p o n d to chemotherapies, and was referred to the A s a h i k a w a M u n i c i p a l Hospital on November 18, 1981, for a precise diagnosis and further care. The hematologic data were as follows: WBC 5.38 x 104/mm 3 (leukemic cells, 79%); RBC 3.07 x 108/ram3; h e m o g l o b i n 9.4g/dl; hematocrit 28.8%; and platelets 3.71 × 105/mm 3. The bone marrow aspirate s h o w e d 7 x 104/mm 3 nucleated cells (leukemic cells, 74%) and 25/mm 3 megakaryocytes, without detectable erythroid cells. The leukemic cells were variable in size, showing decreased cytoplasm/nucleus ratio, and the b a s o p h i l i c c y t o p l a s m without granulation. The nucleus showed finely d i s p e r s e d chromatin and p r o m i n e n t nucleoli. The existence of the hiatus leukemicus indicated the poor maturation of the leukemic cells. The neutrophil alkaline p h o s p h a t a s e was found to be low (rate, 12%; score, 23), camFrom the Chromosome Research Unit, Faculty of Science, Hokkaido University, Sapporo (T.Y., M.S.), • and the Department of Internal Medicine. Asahikawa Municipal Hospital, Asahikawa (T.K.), Japan. Address requests for reprints to Dr. Motomichi Sasaki, Chromosome Research Unit, Faculty of Science, Hokkaido University, North 10, West 8, Sapporo 060, Japan. Received May 25, 1985; accepted August 19, 1985. 343 © 1986 Elsevier Science Publishing Co., Inc. 52 Vanderbilt Ave., New York. NY 10017
Cancer Genet Cytogenet 21:343-345(1986) 0165-4608/86/$03.50
344
T. Yamada, M. Sasaki, and T. Kawamura pared with the control value (rate, 97%: score 331), and platelet function tests revealed a marked decrease in the a d h e s i v e n e s s to glass beads as well as in the aggregation rate as measured with a d e n o s i n e d i p h o s p h a t e , suggesting the possible precedence of chronic phase. The leukemic cells showed negative reactions to peroxidase, periodic acid-Schiff, and esterase, la antigen [6], c o m m o n ALL antigen [7], surface Ig, and the monoclonal antibody, l,eu-1 [8] were all negative and no cells formed E-rosettes, suggesting that the leukemic cells were of nonlymphoid cell origin. The patient, thus, was diagnosed to be in the acute phase of CML. Combination therapies with vindesin plus L-asparaginase plus predonine, and aclarubicin plus behenoyl-ara C were unsuccessful. On April 14, 1982 (8 months after the first admission), the patient died of p n e u m o n i a .
CYTOGENETIC FINDINGS Chromosomal analysis was performed on short-term cultures of bone marrow cells, on November 20, 1981. Twenty metaphases were analyzed after Q-banding, among which 17 showed a 47.XY, + 11 karyotype (Fig. 1 ), while the remaining three variant cells showed a random loss ( - 7 , - 1 4 , or - 1 7 ) from the stem line karyotype probably due to artifacts. We did not examine the constitutional karyotype of this patient but, considering he had a normal phenotype, the trisomic cells were thought to be leukemic cells. DISCUSSION There have been no reported cases of CML with trisomy 11 as the sole abnormality. Although four of the five reported cases of blood disorders with trisomy 11 had karyotypically normal cells in the bone marrow samples, our case and one other Figure 1
Representative karyotype of a bone marrow (:ell with 47,XY,- 11.
Ph-Negatiw; CML
345
r e p o r t e d case 13] c o n t a i n e d (;xclusively t r i s o m i c 11 cells in the b o n e m a r r o w . It is u n k n o w n , h o w e v e r , if the t r i s o m i c cells w e r e f o r m e d in the stem cells, or a c q u i r e d d u r i n g m a l i g n a n t g r o w t h , or as a result of c h e m o t h e r a p i e s . It is i n t e r e s t i n g to note that P h - n e g a t i v e CML cases are g e n e r a l l y d i p l o i d w i t h o u t c h a r a c t e r i s t i c or consistent k a r y o t y p i c c h a n g e e x c e p t for the i n c i d e n t a l o c c u r r e n c e of t r i s o m y 8 and s o m e o t h e r less c o m m o n c h a n g e s i n c l u d i n g a m i s s i n g Y [9]. Recent reports point to occasional a s s o c i a t i o n of t h r o m b o c y t o p e n i a a n d / n r f u n c t i o n a l r e d u c t i o n of platelets with + 11 or 11q + [5, 10, 11 ]. O u r patient e x h i b i t e d a c o n s i d e r a b l e extent of functional r e d u c t i o n of platelets, in spite of the fact that the platelet c o u n t was h i g h e r than the n o r m a l value. F u r t h e r a c c u m u l a t i o n of data is n e e d e d to better u n d e r s t a n d the p a t h o g e n i c role of t r i s o m y 11 in v a r i o u s h e m a t o l o g i c disorders. W h e t h e r or not the h u m a n p r o t o o n c o g e n e c-Ha-ras 1, w h i c h is located on the short arm of t:hrc*m o s o m e #11 [12], is a m p l i f i e d in the t r i s o m i c 11 cells is a n o t h e r q u e s t i o n in need of a solution. Supported in par! by a Grant-in-Aid for Cancer Research from the Ministry of I':ducation, Science and Culture, Japan.
REFERENCES 1. Yunis JJ, Bloomfield CD, Ensrud K (1981): All patients with acute nonlymphocytic leukemia may have a chromosomal defect. N Engl J Med 16:135--139. 2. Fitzgerald PH, Morris CM. Fraser GJ, Giles LM, Hamer JW, Heaton DC, Beard MEJ (1983): Nonrandom cytogenetic changes in New Zealand patients with acute myeloid h;ukemia. Cam:er Genet Cytogenet 8:51-66. 3. Li YS, Khalid G, Hayhoe FGJ (1983): Correlation between chromosomal pattern, cytological subtypes, response to therapy, and survival in acute myeloid leukaemia. Scand J Haematol 30:265-277. 4. liagemeijer A, Hahlen K, Abels ] (1981J: Cytogenetic follow-up of patients with uonlymphocytic leukemia. II. Acute nonlymphocytic leukemia. Cancer Genet Cytogenet 3:109124. 5. Gangji 13, Noseda A, Wybran J, Verhest A {1985}: Trisomy 11 in preleukemia. Cancer Cenet Cytogenet 14:119- 123. 6. Billing R], Safani M, Peterson P (1976): Isolation and characterization of human B cell alloantigens. J lmmunol 117:1589- 1593. 7. Greaves MF. Brown (;, Rapson NT, Lister TA (1975): Antisera to acute lymphoblastic leukemia cells. Clin Immunol lmmunopathol 4:67-84. 8. Wang ('Y, Good RA, Ammirati P, Dymbort G, Evans RI, (1980): hlentificatiou of a p69,71 complex expressed on human T cells sharing determinants with B-type chronic: lymphatic: leukemic cells. J. Exp Med 151:1539-1544. 9. Kohno S, Abe S, Sandberg AA (1979]: The chromosomes and causation of human cancer and leukemia: XXXVIII. Cytogenetic experience in Phi-negative chronic myelocytic leukemia [CMI,). Am J Hemato] 7:281-291. 10. Tricot G, Griel A, Verwilghen RI, (1982): Thrombocytopenia as presenting symptom of preleukaemia in 3 patients. Stand J Haematol 28:243-250. 11. Tricot G, Van Den Berghe H (1982): Isolated peripheral thrombocytopenia as presenting symptom in preleukemia: A report of two cases with 11q+. Cancer Genet Cytogenet 5:147-151, 12. de Martinville B. Giacalone J, Shih C, Weinberg RA, Francke V (1983): Oncogene from human EJ bladder carcinoma is located on the short arm of chromosome 11. Science 219:498-501.