Trisomy 4 in a Case of Acute Lymphocytic Leukemia (L1) Keiko Hodohara, Yoshihide Fujiyama, Tetsuya Inoue, Mitsuyuki Niwakawa, Katsuyuki Kitoh, Akira Andoh, Tadao Bamba, Shiro Hosoda, and Tatsuo Abe
ABSTRACT: T r i s o m y 4 has been identified previously as a chromosome abnormality associated with acute n o n l y m p h o c y t i c l e u k e m i a (ANLL) with m y e l o m o n o c y t i c lineage and in m y e l o d y s p l a s t i c syndromes (MDS). We report a case of acute l y m p h o c y t i c leukemia (ALL) (French-American-British, FAB L1) in a 42-year-old Japanese man, with trisomy 4 as the sole chromosomal anomaly. I m m u n o p h e n o t y p i cally, the l e u k e m i c blasts demonstrated reactivity with CD2, CD5, and CD7 and indicated an early stage of T cell.
INTRODUCTION Cytogenetic studies have shown that most patients with leukemia and lymphoma have chromosome abnormalities, which in many cases are specific for the morphologic type and have prognostic significance. Recently, trisomy 4 was described as a new chromosome abnormality that characterizes a subgroup of acute nonlymphocytic leukemia (ANLL) and myelodysplastic syndromes (MDS) [1-3]. We report a case of trisomy 4 with L1 ALL, which was defined morphologically and immunochemically.
CASE REPORT A 42-year-old Japanese man was referred to our university hospital in December 1988 because of severe cough and dyspnea. Physical examination showed enlargement of lymph nodes in the cervical, axillary, and inguinal regions and hepatosplenomegaly. Chest roentgenogram showed marked enlargement of bilateral hilar lymph nodes. Hematologic data were as follows: red blood cell (RBC) count 302 x 104//xl, hemoglobin (Hb) level 10.4 g/dl, hematocrit (Ht) 29.8%, platelet count 91,000/~1, and white blood cell (WBC) count 18,800/txl with 78% blasts, 2% band neutrophils, 2% segmented neutrophils, 1% eosinophils, 16% lymphocytes, and 1% atypical lymphocytes. HTLV-1 was negative. The bone marrow (BM) aspirate was normocellular, with massive infiltration by blast cells. A myelogram showed 94%
From the Second Department of Internal Medicine, Shiga University of Medical Science (K. H., Y. F., T, I., M. N., K. K., A. A., T. B., S. H.), and the Department of Hygiene, Kyoto Prefectural University of Medicine (T. A.), Kyoto, Japan. Address reprint requests to: Keiko Hodohara, The Second Department of Internal Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Japan 520-21. Received February 28, 1992; accepted May 13, 1992.
88 Cancer Genet Cytogenet62:88 91 (1992) 0165-4608/92/$05.00
blasts, 5% lymphocytes, and 1% erythroid cells. WrightGiemsa staining of leukemic blasts is shown in Figure 1. These blasts were less than twice the size of a small lymphocyte, negative for peroxidase and periodic acid-Schiff (PAS) staining and positive for acid phosphatase reaction. They had a high nuclear to cytoplasmic (N/C) ratio and inconspicuous nucleoli. Diagnosis of acute lymphocytic leukemia, French-American-British (FAB) L1 was made. The patient received induction therapy consisting of adriamycin, vincristine, L-asparaginase, and prednisolone. Complete remission (CR) was obtained after two cycles of treatment. Monthly courses of maintenance treatment with vincristine, L-asparaginase, and cyclophosphamide were then given, but he relapsed in April 1990. The leukemic blasts demonstrated the same morphology as that at initial examination. Second "myeloid-type" induction therapy consisting of daunorubicin, etoposide, enocitabine, and prednisolone failed to achieve CR despite prolongation of the neutropenic period. A combination of chemotherapy with daunorubicine, vincristine, L-asparaginase, and prednisolone that has been developed for the high-risk group of ALL was then given. The patient achieved remission after one course of the induction therapy and received consolidation treatment with cyclophosphamide, mercaptopurine, and cytarabine. At the last hematologic follow-up in December 1991, he was still in CR. There was no history of exposure to radiation, toxic chemicals, or unusual drugs.
Cytogenetic Analysis Cytogenetic analysis was performed at diagnosis in 1988 and at first relapse in 1990. Direct chromosome preparations of 48-hour unstimulated cultures of BM aspirates were used. Karyotyping was performed by a procedure that included treatment with trypsin and Giemsa staining to obtain Gbanding. Analysis showed trisomy 4 as the sole anomaly in four of 14 metaphases at diagnosis and in all metaphases at :c 1992 Elsevier SciencePublishing Co,, inc. 655 Avenueof the Americas, New York, NY lO01a
Trisomy 4 in ALL
Figure 1
89
Wright-Giemsa stain of bone marrow aspirate showing L1 type lymphoblasts.
rates separated by Ficoll-Hypaque gradient were incubated with FITC-conjugated MoAbs (Becton Dickinson, California). Fluorescence was evaluated by fluorescence-activated cell sorter. The leukemic blasts reacted with early T-cell antigens (CD2, CD5 and CD7), but not with B cell antigens (CD19 and CD20) or myelomonocyte-associated antigens (CD13, CD14, and CD33).
first relapse (Fig. 2). The patient's karyotype at remission was 46,XY.
Immunologic Marker Studies Cell surface antigens were detected by a standard direct immunofluorescence assay with FITC-conjugated monoclonal antibodies (MoAbs). Mononuclear cells of BM aspi-
Figure 2
Karyotype with 47 chromosome and trisomy 4.
.....
1
2
3
6
7
8
13
14
15
9
12 •
4
5
10
11
12
16
17
18
tt 19
20
21
22
x¥
90
K. Ho(h)bara eta[.
Table 1 Patient
S u m m a r y of reported patients with trisomy 4 Age (yr)/sex
1 2 3 4 5
17/F 64/F 56/F 15/M 58/F
6
25/F
7
53/F
8
74/F
9 10 11 12 13 14 15
54/M 25/M 64/M 58/F
34/F 54/F
16 17
75/F 71/F 72/F
18 19 20 21 22 23 24 25 26 27 28 29 30 31
51/F 60/F 42/M 70/M 50/F 52/M 11/M 13 mo/M 67/M 22/M 69/M 61/F 5/F 42/M
FAB type M2 M4 M4 M4 RAEB in T M4 M4 M4 M2 or M4 M1 M2 M2 M2 M2 or M4 M1 M4 M4 M4 M2 M2 M2 M2 M4 M1 ALJL M4 M2 M4 AUL Biphenotypic L1
Ref. [1]
[2]
]3] [4[ [5] I6] [71 ]8] [9] [101 [11] [12] [13]
[14l [151 [16] Present study
Investigators in previous studies suggested that trisomy 4 may be associated specifically with acute myelogenous leukemia. Recently, Britton et al. [16] reported a case of acute biphenotypic leukemia with trisomv 4 as the sole chromosome anomaly. The leukemic blasts they reported had m a i n l y lymphoid morphology but demonstrated sim u l t a n e o u s reactivity with myeloid-associated and lymphoid cell surface markers. The acute leukemia in these cases indicated that the target cell associated with trisomy 4 might be an pluripotential stem cell capable of differentiating along both the granulomonocytic and lymphoid lineages. Despite its conspicuous anomaly, trisomy 4 associated with acute leukemia was never described until 1986. Sandberg et al. [171 suggested a possible association of trisomy 4 with some new e n v i r o n m e n t a l or toxic exposure in the last 1-2 decades [17], but we noted no such exposure in our patient. Most leukemic patients have chromosome abnormalities specific for the morphologic type. Rowley reported that identification of certain chromosome anomalies in leukemic patients could contribute to an u n d e r s t a n d i n g of the role of chromosome changes in m a l i g n a n c y [18]. Trisomy 4 has been reported to be related to the increased production of some factors controlled by genes located on this chromosome [19]. Three genes have been m a p p e d on chromosome 4, one coding for the epidermal growth factor [20], one coding for the k i t oncogene [20], and the other coding for the T-cell growth factor (TCGF) interleukin-2 [21]. Trisomy 4 may have involved proliferation of the neoplastic cells in these cases by amplification of TCGF.
Abbreviations: FAB, French-American-British;RAEB. refractory anemia
with excess of blasts.
DISCUSSION We report a case of ALL with the chromosome abnormality of trisomy 4. Since Mecucci et al. [1] first described four cases with trisomy 4 in ANLL and MDS, 30 cases with this a n o m a l y have been reported {Table 1). Because most reported cases with trisomy 4 had AML M2 or M4, trisomy 4 has been believed to arise in at least an early myeloid hematopoietic stem cell capable of differentiating along either the monocytic or granulocytic lineage [1-3]. Our patient was identified as having ALL L1 by morphologic criteria of the FAB classification. The leukemic blasts were small, with a high N/C ratio, a nucleus of regular shape, and i n c o n s p i c u o u s nucleoli. Cytochemical studies showed that the blasts reacted only with acid phosphatase. I m m u n o c y t o c h e m i c a l studies indicated that the cells could arise from an early thymic T cell on the basis of the positivity with MoAbs of CD2, CD5, and CD7. In T-ALL, PAS reaction is weak or negative in association with its high proliferative rate, and acid phophatase reaction has been considered specific for T lineage. Thus, the morphology, cytochemical, and i m m u n o c y t o c h e m i c a l reactions in our patient were most consistent with a diagnosis of ALL L1 of T-cell type.
REFERENCES 1 Meccuci C, Van Orshoven A, Tricot G, Michaux JL, Dellanoy A, Van Den Berghe H (1986): Trisomy 4 identifies a subset of acute leukemias. Blood 67:1328-1332. 2. Sandberg AA, Morgan R, Sait, SNJ, Berger R, Flandrin G, Schrier S, Hecht F (1987): Trisomy 4: An entity within acute nonlymphocytic leukemia. Cancer Genet Cytogenet 26:117-125. 3. Prieto F, Badia L, Angeles Orts M, Dieguez L, Amigo V (1987}: Trisomy 4: Another specific anomaly in acute nonlymphocytic leukemia. Cancer Genet Cytogenet 26:171-173. 4. Horsman DE, Pantzar JT. Kalousek DK (1988): Trisomy 4 in acute nonlymphocytic leukemia. Cancer Genet Cytogenet 36:155-157. 5. Fujishita M, Miyagi T, Takeuchi T, Kubonishi I, Niiya K, Taguchi H, Ohtsuki Y, Miyoshi I (1988): Trisomy 4 in a case of acute nonlymphncyticleukemia (M2). Cancer Genet Cytogenet 34:281-284. 6. Hoyle CF, Boughton BJ, Hayhoe FGJ (1988): Two further cases of acute myeloid leukemia with trisomy 4. Cancer Genet Cytogenet 34:29-32. 7. Juneja S. Brown J, Ding JC, Garson OM (1988): Trisomy 4 in acute nonlymphocytic leukemia. Cancer Genet Cytogene! 34:25-28. 8. Suciu S, Weh HJ, Kuse R, Meier CB, Hossfeld DK (1988): Trisomy 4 in two cases of acute myelomonocytic leukemia. Cancer Genet Cytogenet 33:19-23. 9. Yokota S, Taniwaki M, Okuda T, Maekawa T, Nishida K, Misawa S, Takino T, Abe T, Urata Y (1989): Acute nonlymphocytk
T r i s o r n y 4 i n ALL
10.
11.
12.
13.
14.
15.
leukemia (M2) with chromosome abnormality trisomy 4 developing eight years after radiation therapy for breast cancer. Blut 58:27-31. Sakano S, Hirajima N, Noda T, Nitta M (1989): Chromosomal abnormality of trisomy 4 in a patient with acute nonlymphocytic leukemia (FAB:M2). Jpn J Clin Hematol 30:1987-1991. Parry SH, Gibbons B, Czepulkowski BH, Amess JA, Oxley VE (1989): A further case of acute myelogenous leukemia with trisomy 4 and double minutes. Cancer Genet Cytogenet 39:295-297. Temperani P, Zucchini P, Artusi T, Sacchi S, Emilia G (1989): Acute nonlymphocytic leukemia with trisomy 4. Cancer Genet Cytogenet 41:203-205. T h o m p s o n PW, T h o m p s o n EN, Whittaker JA (1989): Four cases of acute leukemia with trisomy 4. Cancer Genet Cytogenet 43:211-217. Weber E, Nowothy H, Haas OA, Kasparu H, Grois N, Lutz D (1990): Trisomy 4: A specific karyotype anomaly in primary and secondary acute myeloid leukemia. Leukemia 4:219-221. Kao YS, McCormick C, Vial R (1990): Trisomy 4 in a case
91
of acute undifferentiated myeloblastic leukemia with handmirror cells. Cancer Genet Cytogenet 45:265-268. 16. Britton V, Kwan YL, White L, Yip MY (1990): Trisomy 4 in a case of acute biphenotypic leukemia. Cancer Genet Cytogenet 47:265-269. 17. Sandberg AA, Vand Den Berghe H, Hecht F (1987): Trisomy 4 in hematologic disorders. Cancer Genet Cytogenet 26:175. 18. Rowley JD (1973): A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243:290-293. 19. Sporn MB, Roberts AB (1985): Autocrine growth factors and cancer. Nature 313:745-747. 20. Zabel BU, Eddy RL, Lally PA, Scott J, Bell GI, Shows TB (1985): Chromosomal locations of the h u m a n and mouse genes for precursors of epidermal growth factor and the subunit of nerve growth factor. Proc Natl Acad Sci USA 82:469-473. 21. Seigel LJ, Harper ME, Wong-Staal F, Gallo R, Nash WG, O'Brien SJ (1984): Location on h u m a n chromosome 4q and feline chromosome B1, Science 223:175-178.
ABSTRACT: T r i s o m y 4 has been identified previously as a chromosome abnormality associated with acute n o n l y m p h o c y t i c l e u k e m i a (ANLL) with m y e l o m o n o c y t i c lineage and in m y e l o d y s p l a s t i c syndromes (MDS). We report a case of acute l y m p h o c y t i c leukemia (ALL) (French-American-British, FAB L1) in a 42-year-old Japanese man, with trisomy 4 as the sole chromosomal anomaly. I m m u n o p h e n o t y p i cally, the l e u k e m i c blasts demonstrated reactivity with CD2, CD5, and CD7 and indicated an early stage of T cell.
INTRODUCTION Cytogenetic studies have shown that most patients with leukemia and lymphoma have chromosome abnormalities, which in many cases are specific for the morphologic type and have prognostic significance. Recently, trisomy 4 was described as a new chromosome abnormality that characterizes a subgroup of acute nonlymphocytic leukemia (ANLL) and myelodysplastic syndromes (MDS) [1-3]. We report a case of trisomy 4 with L1 ALL, which was defined morphologically and immunochemically.
CASE REPORT A 42-year-old Japanese man was referred to our university hospital in December 1988 because of severe cough and dyspnea. Physical examination showed enlargement of lymph nodes in the cervical, axillary, and inguinal regions and hepatosplenomegaly. Chest roentgenogram showed marked enlargement of bilateral hilar lymph nodes. Hematologic data were as follows: red blood cell (RBC) count 302 x 104//xl, hemoglobin (Hb) level 10.4 g/dl, hematocrit (Ht) 29.8%, platelet count 91,000/~1, and white blood cell (WBC) count 18,800/txl with 78% blasts, 2% band neutrophils, 2% segmented neutrophils, 1% eosinophils, 16% lymphocytes, and 1% atypical lymphocytes. HTLV-1 was negative. The bone marrow (BM) aspirate was normocellular, with massive infiltration by blast cells. A myelogram showed 94%
From the Second Department of Internal Medicine, Shiga University of Medical Science (K. H., Y. F., T, I., M. N., K. K., A. A., T. B., S. H.), and the Department of Hygiene, Kyoto Prefectural University of Medicine (T. A.), Kyoto, Japan. Address reprint requests to: Keiko Hodohara, The Second Department of Internal Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Japan 520-21. Received February 28, 1992; accepted May 13, 1992.
88 Cancer Genet Cytogenet62:88 91 (1992) 0165-4608/92/$05.00
blasts, 5% lymphocytes, and 1% erythroid cells. WrightGiemsa staining of leukemic blasts is shown in Figure 1. These blasts were less than twice the size of a small lymphocyte, negative for peroxidase and periodic acid-Schiff (PAS) staining and positive for acid phosphatase reaction. They had a high nuclear to cytoplasmic (N/C) ratio and inconspicuous nucleoli. Diagnosis of acute lymphocytic leukemia, French-American-British (FAB) L1 was made. The patient received induction therapy consisting of adriamycin, vincristine, L-asparaginase, and prednisolone. Complete remission (CR) was obtained after two cycles of treatment. Monthly courses of maintenance treatment with vincristine, L-asparaginase, and cyclophosphamide were then given, but he relapsed in April 1990. The leukemic blasts demonstrated the same morphology as that at initial examination. Second "myeloid-type" induction therapy consisting of daunorubicin, etoposide, enocitabine, and prednisolone failed to achieve CR despite prolongation of the neutropenic period. A combination of chemotherapy with daunorubicine, vincristine, L-asparaginase, and prednisolone that has been developed for the high-risk group of ALL was then given. The patient achieved remission after one course of the induction therapy and received consolidation treatment with cyclophosphamide, mercaptopurine, and cytarabine. At the last hematologic follow-up in December 1991, he was still in CR. There was no history of exposure to radiation, toxic chemicals, or unusual drugs.
Cytogenetic Analysis Cytogenetic analysis was performed at diagnosis in 1988 and at first relapse in 1990. Direct chromosome preparations of 48-hour unstimulated cultures of BM aspirates were used. Karyotyping was performed by a procedure that included treatment with trypsin and Giemsa staining to obtain Gbanding. Analysis showed trisomy 4 as the sole anomaly in four of 14 metaphases at diagnosis and in all metaphases at :c 1992 Elsevier SciencePublishing Co,, inc. 655 Avenueof the Americas, New York, NY lO01a
Trisomy 4 in ALL
Figure 1
89
Wright-Giemsa stain of bone marrow aspirate showing L1 type lymphoblasts.
rates separated by Ficoll-Hypaque gradient were incubated with FITC-conjugated MoAbs (Becton Dickinson, California). Fluorescence was evaluated by fluorescence-activated cell sorter. The leukemic blasts reacted with early T-cell antigens (CD2, CD5 and CD7), but not with B cell antigens (CD19 and CD20) or myelomonocyte-associated antigens (CD13, CD14, and CD33).
first relapse (Fig. 2). The patient's karyotype at remission was 46,XY.
Immunologic Marker Studies Cell surface antigens were detected by a standard direct immunofluorescence assay with FITC-conjugated monoclonal antibodies (MoAbs). Mononuclear cells of BM aspi-
Figure 2
Karyotype with 47 chromosome and trisomy 4.
.....
1
2
3
6
7
8
13
14
15
9
12 •
4
5
10
11
12
16
17
18
tt 19
20
21
22
x¥
90
K. Ho(h)bara eta[.
Table 1 Patient
S u m m a r y of reported patients with trisomy 4 Age (yr)/sex
1 2 3 4 5
17/F 64/F 56/F 15/M 58/F
6
25/F
7
53/F
8
74/F
9 10 11 12 13 14 15
54/M 25/M 64/M 58/F
34/F 54/F
16 17
75/F 71/F 72/F
18 19 20 21 22 23 24 25 26 27 28 29 30 31
51/F 60/F 42/M 70/M 50/F 52/M 11/M 13 mo/M 67/M 22/M 69/M 61/F 5/F 42/M
FAB type M2 M4 M4 M4 RAEB in T M4 M4 M4 M2 or M4 M1 M2 M2 M2 M2 or M4 M1 M4 M4 M4 M2 M2 M2 M2 M4 M1 ALJL M4 M2 M4 AUL Biphenotypic L1
Ref. [1]
[2]
]3] [4[ [5] I6] [71 ]8] [9] [101 [11] [12] [13]
[14l [151 [16] Present study
Investigators in previous studies suggested that trisomy 4 may be associated specifically with acute myelogenous leukemia. Recently, Britton et al. [16] reported a case of acute biphenotypic leukemia with trisomv 4 as the sole chromosome anomaly. The leukemic blasts they reported had m a i n l y lymphoid morphology but demonstrated sim u l t a n e o u s reactivity with myeloid-associated and lymphoid cell surface markers. The acute leukemia in these cases indicated that the target cell associated with trisomy 4 might be an pluripotential stem cell capable of differentiating along both the granulomonocytic and lymphoid lineages. Despite its conspicuous anomaly, trisomy 4 associated with acute leukemia was never described until 1986. Sandberg et al. [171 suggested a possible association of trisomy 4 with some new e n v i r o n m e n t a l or toxic exposure in the last 1-2 decades [17], but we noted no such exposure in our patient. Most leukemic patients have chromosome abnormalities specific for the morphologic type. Rowley reported that identification of certain chromosome anomalies in leukemic patients could contribute to an u n d e r s t a n d i n g of the role of chromosome changes in m a l i g n a n c y [18]. Trisomy 4 has been reported to be related to the increased production of some factors controlled by genes located on this chromosome [19]. Three genes have been m a p p e d on chromosome 4, one coding for the epidermal growth factor [20], one coding for the k i t oncogene [20], and the other coding for the T-cell growth factor (TCGF) interleukin-2 [21]. Trisomy 4 may have involved proliferation of the neoplastic cells in these cases by amplification of TCGF.
Abbreviations: FAB, French-American-British;RAEB. refractory anemia
with excess of blasts.
DISCUSSION We report a case of ALL with the chromosome abnormality of trisomy 4. Since Mecucci et al. [1] first described four cases with trisomy 4 in ANLL and MDS, 30 cases with this a n o m a l y have been reported {Table 1). Because most reported cases with trisomy 4 had AML M2 or M4, trisomy 4 has been believed to arise in at least an early myeloid hematopoietic stem cell capable of differentiating along either the monocytic or granulocytic lineage [1-3]. Our patient was identified as having ALL L1 by morphologic criteria of the FAB classification. The leukemic blasts were small, with a high N/C ratio, a nucleus of regular shape, and i n c o n s p i c u o u s nucleoli. Cytochemical studies showed that the blasts reacted only with acid phosphatase. I m m u n o c y t o c h e m i c a l studies indicated that the cells could arise from an early thymic T cell on the basis of the positivity with MoAbs of CD2, CD5, and CD7. In T-ALL, PAS reaction is weak or negative in association with its high proliferative rate, and acid phophatase reaction has been considered specific for T lineage. Thus, the morphology, cytochemical, and i m m u n o c y t o c h e m i c a l reactions in our patient were most consistent with a diagnosis of ALL L1 of T-cell type.
REFERENCES 1 Meccuci C, Van Orshoven A, Tricot G, Michaux JL, Dellanoy A, Van Den Berghe H (1986): Trisomy 4 identifies a subset of acute leukemias. Blood 67:1328-1332. 2. Sandberg AA, Morgan R, Sait, SNJ, Berger R, Flandrin G, Schrier S, Hecht F (1987): Trisomy 4: An entity within acute nonlymphocytic leukemia. Cancer Genet Cytogenet 26:117-125. 3. Prieto F, Badia L, Angeles Orts M, Dieguez L, Amigo V (1987}: Trisomy 4: Another specific anomaly in acute nonlymphocytic leukemia. Cancer Genet Cytogenet 26:171-173. 4. Horsman DE, Pantzar JT. Kalousek DK (1988): Trisomy 4 in acute nonlymphocytic leukemia. Cancer Genet Cytogenet 36:155-157. 5. Fujishita M, Miyagi T, Takeuchi T, Kubonishi I, Niiya K, Taguchi H, Ohtsuki Y, Miyoshi I (1988): Trisomy 4 in a case of acute nonlymphncyticleukemia (M2). Cancer Genet Cytogenet 34:281-284. 6. Hoyle CF, Boughton BJ, Hayhoe FGJ (1988): Two further cases of acute myeloid leukemia with trisomy 4. Cancer Genet Cytogenet 34:29-32. 7. Juneja S. Brown J, Ding JC, Garson OM (1988): Trisomy 4 in acute nonlymphocytic leukemia. Cancer Genet Cytogene! 34:25-28. 8. Suciu S, Weh HJ, Kuse R, Meier CB, Hossfeld DK (1988): Trisomy 4 in two cases of acute myelomonocytic leukemia. Cancer Genet Cytogenet 33:19-23. 9. Yokota S, Taniwaki M, Okuda T, Maekawa T, Nishida K, Misawa S, Takino T, Abe T, Urata Y (1989): Acute nonlymphocytk
T r i s o r n y 4 i n ALL
10.
11.
12.
13.
14.
15.
leukemia (M2) with chromosome abnormality trisomy 4 developing eight years after radiation therapy for breast cancer. Blut 58:27-31. Sakano S, Hirajima N, Noda T, Nitta M (1989): Chromosomal abnormality of trisomy 4 in a patient with acute nonlymphocytic leukemia (FAB:M2). Jpn J Clin Hematol 30:1987-1991. Parry SH, Gibbons B, Czepulkowski BH, Amess JA, Oxley VE (1989): A further case of acute myelogenous leukemia with trisomy 4 and double minutes. Cancer Genet Cytogenet 39:295-297. Temperani P, Zucchini P, Artusi T, Sacchi S, Emilia G (1989): Acute nonlymphocytic leukemia with trisomy 4. Cancer Genet Cytogenet 41:203-205. T h o m p s o n PW, T h o m p s o n EN, Whittaker JA (1989): Four cases of acute leukemia with trisomy 4. Cancer Genet Cytogenet 43:211-217. Weber E, Nowothy H, Haas OA, Kasparu H, Grois N, Lutz D (1990): Trisomy 4: A specific karyotype anomaly in primary and secondary acute myeloid leukemia. Leukemia 4:219-221. Kao YS, McCormick C, Vial R (1990): Trisomy 4 in a case
91
of acute undifferentiated myeloblastic leukemia with handmirror cells. Cancer Genet Cytogenet 45:265-268. 16. Britton V, Kwan YL, White L, Yip MY (1990): Trisomy 4 in a case of acute biphenotypic leukemia. Cancer Genet Cytogenet 47:265-269. 17. Sandberg AA, Vand Den Berghe H, Hecht F (1987): Trisomy 4 in hematologic disorders. Cancer Genet Cytogenet 26:175. 18. Rowley JD (1973): A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243:290-293. 19. Sporn MB, Roberts AB (1985): Autocrine growth factors and cancer. Nature 313:745-747. 20. Zabel BU, Eddy RL, Lally PA, Scott J, Bell GI, Shows TB (1985): Chromosomal locations of the h u m a n and mouse genes for precursors of epidermal growth factor and the subunit of nerve growth factor. Proc Natl Acad Sci USA 82:469-473. 21. Seigel LJ, Harper ME, Wong-Staal F, Gallo R, Nash WG, O'Brien SJ (1984): Location on h u m a n chromosome 4q and feline chromosome B1, Science 223:175-178.
