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Translocation X;10 in a case of congenital acute monocytic leukemia
SHORT COMMUNICATION Translocation X;10 in a Case of Congenital Acute Monocytic Leukemia John Weis, Victoria DeVito, Lee Allen, David Linder, and Ellen Magenis
ABSTRACT: Unusual cytogenetic findings were noted in the leukemic cells from a patient with congenital acute monocytic leukemia (AMol or M5, according to the FAB classification), whereas, the chromosomes of cultured skin fibroblasts were normal. G-banded karyotypes of leukemic cells showed an X-autosome translocation, 46,X,t(X;lO)(Xpter-~q13::10q11.2--,qter)(10pter--~ q11.2::Xq28-*q13::Xq28--~qter). Review of reported cases of acute nonlymphocytic leukemia (ANLL) with rearrangements involving chromosomes #10 or X showed a high frequency of abnormalities of the short arm of #10 in myelomonocytic (M4) and monocytic (M5) leukerajas, particularly in patients less than 2-yr-of-age. Although previously reported cases of ANLL in infants are predominantly of these types, the translocation observed in this case is unique. Fragile sites known to exist on chromosomes #10 and X are not associated with neoplasia and, except for Xq27-28, were not at the breakpoints of the case presented. The precise location of a human cellular oncogene recently identified on the X chromosome remains unknown.
INTRODUCTION Among the types of leukemia that are associated with specific chromosomal changes, acute monocytic leukemia (AMoL or M5, according to the FAB classification [1]) has been found to involve (in a large n u m b e r of cases) rearrangements of the long arm of chromosome #11, most frequently at b a n d 11q23 [2-4]. X-autosome translocations in association with leukemias or other neoplastic diseases are very u n c o m m o n [5]. We present a G-banded chromosome study of leukemic cells with a translocation involving chromosomes # 1 0 and X from a n e w b o r n infant with skin lesions, hepatosplenomegaly, and high n u m b e r s of circulating immature cells. The patient was diagnosed as having AMoL (M5) on the basis of morphologic and cytochemical examination of peripheral blood smears. CASE REPORT AND CYTOGENETIC FINDINGS The infant was the 2 Kg product of a 35-wk pregnancy of a 21-yr-old American Indian mother, complicated by premature labor at 30 wk, requiring ritodrine hydro-
From the Departmentsof Pathology, Pediatrics, and Medical Genetics,OregonHealth Sciences University, Portland, OR Address requests for reprints to Dr. John Weis, Department of Pathology, Mayo Clinic/ Mayo Foundation, Rochester, MN 55905. Received June 16, 1984; accepted July 30, 1984.
357 © 1985 ElsevierScience PublishingCo., Inc. 52 VanderbiltAve., New York, NY 10017
Cancer Geneticsand Cytogenetics16, 357-364 (1985) 0165-4608/85/$03.30
358
J. Weis et al. chloride until vaginal delivery at 35 wk. There was no maternal exposure to radiation, toxins, infections, or medications--other than ritodrine--during the pregnancy. The mother was gravida 4, para 4, and the three older siblings of the patient were normal. The infant required immediate resuscitation, and was noted to have multiple flat white and nodular skin lesions, and hepatosplenomegaly. On admission, hemoglobin was 11.4 g/dl, platelet count 15,000/ram 3, and WBC count 200,000/ mm 3. Artificial ventilation and blood pressure support with dopamine and dobutamine were required, and a double-volume exchange transfusion was performed for hyperviscosity and anemia. Examination of the infant's Wright-stained peripheral blood smear revealed more than 95% of the nucleated cells to be immature cells with large, often folded or lobulated nuclei. The leukemic cells had abundant cytoplasm with fine azurophilic granulation, and often contained multiple clear vacuoles (Fig. 1). Cytochemical studies included myeloperoxidase, Sudan black, naphthol-ASD-chloroacetate esterase (NASDCA), and alpha-naphthyl-butyrate esterase (ANBE). Testing for NaF inhibition of esterase activity was not done. Positivity of varying intensity was noted in approximately 10% of cells for myeloperoxidase and 50% of cells with Sudan black. Cytochemical staining for ANBE was strikingly positive in all of the leukemic cells, and the NASDCA reaction also was positive, though much more weakly staining, in essentially all of the cells. In our laboratory, significant ANBE-positive staining is restricted to monocytes, which generally are negative for NASDCA. This is also the experience of other investigators who, like us, use fast blue BB (Sigma, St. Louis) as dye coupler in this reaction [6]. In spite of the weakly positive NASDCA reaction, the neoplasm was considered to be pure monocytic (M5), subtype M5b, because of their uniformly monocytoid appearance on Wright-stained blood films. The infant died at 27-hr-of age with unremitting acidosis and cardiac failure. Postmortem examination revealed leukemic infiltration of the infant's heart, lungs, Figure I
AMol cells in Wright-stained peripheral blood smear.
t(X;10) in AMoL
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Figure 2 (A) Karyotype of cell from unstimulated peripheral blood with a translocation involving chromosome #10 and X. (B) Chromosome pairs #10 and X from karyotype in Fig. 2A with schematic drawing showing breakpoints and ,translocation.
360
J. Weis et al. liver, spleen, kidneys, l y m p h nodes, and bone marrow. In addition, the cutaneous lesions noted on p h y s i c a l exam were shown to be nodules of leukemic cells, in some areas associated with subcutaneous fat necrosis. Cytogenetic studies were performed on the infant's u n s t i m u l a t e d p e r i p h e r a l blood and cultured skin fibroblasts. A n a m e t h o p t e r i n - s y n c h r o n i z e d 24-hr culture of peripheral blood was studied following G-banding. Twenty r a n d o m l y selected metaphases from the peripheral blood all exhibited the t(X;10) (Xpter-~q13::10q11.2--~qter)(10pter-~q11.2::Xq28--~q13::Xq28--~qter)(Fig. 2). This abnormality was not seen in 20 mitoses e x a m i n e d from the cultured skin fibroblasts, all of w h i c h were 46,XX.
DISCUSSION AMol (M5) comprises a significant p r o p o r t i o n of acute n o n l y m p h o c y t i c leukemia (ANLL) occurring in neonates and infants less than 1-yr-of-age, and frequently is associated with c h r o m o s o m a l rearrangements involving the long arm of chromosome #11, particularly band 11q23 [2-4, 7-11]. The poorly differentiated form of M5 (M5a or monoblastic) is more strongly associated with this a b n o r m a l i t y than the well differentiated form (M5b or monocytic) [3, 4, 9-11]. In a recent review by Abe et al., most of the other cases of acute leukemia in this age group are either m y e l o m o n o c y t i c or acute l y m p h o b l a s t i c l e u k e m i a (ALL), both of w h i c h also are associated with c h r o m o s o m a l rearrangements involving 11q23 [7]. Six of eight cases of ALL in infants less than 1-yr-of-age c o m p i l e d by those investigators showed t(4;11), w h i c h in four cases was 5(4;11)(q21;23). The m y e l o m o n o cytic nature of t(4;11) infantile acute l e u k e m i a recently has been d e m o n s t r a t e d by Nagasaka et al., confirming observations first reported in 1981 by Parkin et al. [12, 13]. If t(4;11) infantile leukemia is considered to be a subgroup of m y e l o m o n o c y t i c leukemia, then 18 of the 29 cases (62%) reported by Abe et a l , are either monocytic or have a monocytic component. Rearrangements involving c h r o m o s o m e # 1 0 are m u c h less c o m m o n than chromosome #11 in ANLL, and no cases have been reported involving the vicinity of the q11.2 breakpoint in our case. Review of p r e v i o u s l y reported cases of chromosome #10 rearrangements in ANLL show involvement of the short arm in a high percentage of cases, particularly in monocytic (M5) and m y e l o m o n o c y t i c (M4) types of ANLL [11, 14-22]. Although not present in our case, 18 of the 32 reported cases of ANLL with translocations, insertions, or deletions of c h r o m o s o m e # 1 0 with identifiable breakpoints involved the short arm. Of 16 cases of M4 or M5 types of ANLL with c h r o m o s o m e #10 rearrangements and identifiable breakpoints, 12 (75%) had a breakpoint in this region, including all seven cases in patients less than 2-yr-of-age. These data are listed in Table 1. If only M5 classifications are considered, nine of 11 cases showed a rearrangement involving the p11-p15 region. Although our case is an exception, the consistency of this abnormality among other cases with c h r o m o s o m e #10 rearrangements, particularly among cases of M4 and M5 types of ANLL, may be significant. Rearrangements of the X c h r o m o s o m e involving the q13 breakpoint observed in our case have been reported in three cases of ANLL and one case of acute leukemia, not specified as to l y m p h o c y t i c or n o n l y m p h o c y t i c type. Two cases of ANLL not s u b t y p e d as to FAB classification involved the t(X;9)(9qter-~9q32::Xq13-->Xqter) and dic(X;X)(Xpter-~Xq13::Xq13-->Xpter) [23]. Del(X)(q11) was observed in one case of M4 ANLL, and t(X;1)(q13;p12) in one case of acute leukemia, otherwise not specified [23, 24]. Chromosomal abnormalities involving breakpoints have been reported in four cases of m y e l o d y s p l a s t i c syndromes, and an additional case has been identified by
4/mo 6/mo
12/mo 15/mo 37 86
9 6O 2 12/too 10/mo 21/mo 66 16 37
NG °
1 2
3 4 5 6
7 8 9 10 11 12 13 14 15
16
NG
F M F M M F M F F
M F F M
F F
Sex
M5a
M5 M4 M4 M4 M5a M5a M5a M5a M5
M4 M4 M5 M5
M5 M5
FAB
bCase referenced in this review article.
QNG,Not given.
Age
10 s t r u c t u r a l a b n o r m a l i t i e s Karyotype
46,XY,del(lO)(p12),del(11)(q23),der(8),ins(1o)(p12) 46,XY,t(1;9)(q11;q34),t(1o;11)(p14;q14) 46,XY,t(6;10;11)(p22;p14;q14) 47,XX, + 8,t(10;11)(p13;q14) 57-58,XX,+1,+1,+3,-4,-5,+6,+6,-8,+ 11,+12,-17,+19,-20,del(1o)(q24?),+8 to 4acen? frag t(1o;11)(p14;q13)
46,XY / 46,XY,t(10;11)(p14 ;q13 )
44,XY,t(3;5)(qter;q13),t(7;12)(q12;14),t(7;10)(q12;q21),- 8 , - 1 7 , - 1 8 , - 20 46,XX,t(5;10)(q35;q23)
46,XX,t( lO;11){p15;q2273?)
or 9 i n a r , + 1
46,XX,dir ins(10;11)(p11;q23q24?)/54,XX, + 4, + 8, + 12 + 16, + 19, + 20,dir ins(10;11) 51 ,XX, + 3, + 6, + 9, + 19, - 10,del(1)(p22), + del(1)(p22),dup(11)(qllq21), + der(10)t(10;?)(p13 ;?)/ 52,XX,same, + 18 46,XY/46,XY,t(10,11)(p14;q13) 46,XX,t(10;11)(p15;q21) 54,XX, + 1, + 1, + 3, + 6, + 6, + 11, + 12, - 4, - 5, - 8, - 20,del(10)(q24?), + 5mar, + 4ace 46,X,del(Y)(q12), + 2,der(2)t(2;14)(p11.2;q11.2), + iso5p, + 8,t(9;10)(q13;p11.2),del(9)(pterq13),del(10)(p11.2pter),- 1 3 , - 14
M4/M5 ANLL Cases with chromosome
Patient
Table 1
lO
21 30 14 15 11 11 11 11 36
15 37 b 19 20
14 14
Reference
O3 C3~
362
1. Weis et al.
the Mayo Clinic investigators subsequent to the publication of their report [25-27]. Four of the cases were idiopathic acquired sideroblastic anemias (IASA), one of which progressed to ANLL, M1 subtype. Four of these five cases had isodicentric X chromosomes, and Dewald et al. suggest that the case described by Philips et al. as dic (x;X)(Xpter--~Xq13::Xq13-~Xpter) is probably also an isodicentric X chromosome rather than a translocation dicentric X chromosome, because of the presence of a normal X chromosome in the same karyotype (23, 25-27). Two cases of ANLL with chromosomal rearrangements involving the Xq28 breakpoint seen in our case have been reported, both of which were FAB type M3. In one case t(X;9)(q28;q22) was present in addition to t(15;17) in the leukemic cells [28]. The other case had two separate malignant clones, one with t(15;17) and the other with t(X;7)(q28;q21) [29]. One other case of ANLL, FAB type M1 or M2, had leukemic cells with the karyotype 46, X, del(X)(q21), t(5;21)(q13;q22) [30]. In this case, the deletion might have been at the q13 band rather than q21. Recent reports have suggested that the presence of a heritable fragile site may predispose an i n d i v i d u a l with that fragile site to the development of a n e o p l a s m associated with chromosomal rearrangements involving that site [31-33]. Seven of ten patients studied with a subgroup of myelomonocytic leukemia (M4) with bone marrow eosinophilia, whose leukemic cells showed an inversion or deletion of chromosome #16 at band q22 were shown to have a fragile site at this band in their normal cells [31]. Fragile sites at 11q23 in cells from a patient with t(11;14)(q13;q32) small cell l y m p h o m a and at 12q13 in a patient with t(12;14)(q13;q32) l y m p h o m a have also been described [33]. Fragile sites k n o w n to exist on chromosome #10 (at q23.3 and q25.2) and on X (at q27-28) are not associated with neoplastic disease. Although h u m a n cellular oncogenes have been identified at breakpoints involved in chromosomal aberrations associated with several neoplasms [34], n o n e has yet been found on chromosome #10. Recently, a member of the ras family of oncogenes, c-Ha-ras-2, has been assigned to the X chromosome [35]. The question of whether or not the abnormality observed in our case may involve c-Ha-ras-2 must await clarification of this gene's position on the X chromosome.
REFERENCES 1. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C (1976): Proposals for the classification of the acute leukemias. Br J Haematol 33:451-458. 2. Fourth International Workshop on Chromosomes in Leukemia, 1982 (1984): Overview of association between chromosome pattern and cell morphology, age, sex, and race. Cancer Genet Cytogenet 11:265-274. 3. Berger R, Bernheim A, Weh HJ, Daniel MT, Flandrin G (1980): Cytogenetic studies on acute monocytic leukemia. Leukemia Res 4:119-127. 4. Yunis JJ, Bloomfield CD, Ensrud K (1981): All patients with acute nonlymphocytic leukemia may have a chromosomal defect. N Engl J Med 305:135-139. 5. Sandberg AA (1983): The X chromosome in human neoplasia, including sex chromatins and congenital conditions with X chromosome anomalies. In: Cytogenetics of the Mammalian X Chromosome, Alan R. Liss, New York, pp. 459-498. 6. Kass L, Peters CL (1978): Esterases in acute leukemias. A cytochemical and electrophoretic study. Am J Clin Pathol 69:57-61. 7. Abe R, Ryan D, Cecalupo A, Cohen H, Sandberg AA (1983): Cytogenetic findings in congenital leukemia: Case report and review of the literature. Cancer Genet Cytogenet 9:139144. 8. Hagemeijer A, Hahlen K, Sizoo W, Abels J (1982): Translocation (9;11)(p21;q23) in three cases of acute monoblastic leukemia. Cancer Genet Cytogenet 5:95-105.
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9. Fourth International Workshop on Chromosomes in Leukemia, 1982 (1984): Correlation between morphology and karyotype. Cancer Genet Cytogenet 11:275-281. 10. Fourth International Workshop on Chromosomes in Leukemia, 1982 (1984): Rearrange~ merits of 11q. Cancer Genet Cytogenet 11:294-295. 11. Berger R, Bernheim A, Sigaux F, Daniel M-T, Valensi F, Flandrin G (1982): Acute mono~ cytic leukemia chromosome studies. Leukemia Res 6:17-26. 12. Nagasaka M, Maeda S, Maeda H, Chen HL, Kita K, Mabuchi O, Misu H, Matsuo T, Sugiyama T (1983): Four cases of t(4;11) acute leukemia and its myelomonocytic nature in infants. Blood 61:1174-1181. 13. Parkin J, Abrahamson C, McKenna R, Heideman R, Kersey J, Brunning R (1981): t(4;11) Acute leukemia: Ultrastructural and immunological evidence for a myeloid progenitor cell proliferation. Blood 58: 148a, (suppl. 1). 14. Kaneko Y, Rowley JD, Maurer HS, Variakojis D, Woohr JW (1982): Chromosome pattern in childhood acute nonlymphocytic leukemia (ANLL). Blood 60:389-399. 15. Brodeur GM, Williams DL, Kalwinsky DK, Williams KJ, Dahl GV (1983): Cytogenetic features of acute nonlymphocytic leukemia in 73 children and adolescents. Cancer Genet Cytogenet 8:93-105. 16. Hagemeijer A, Hahlen K, Abels J (1981): Cytogenetic follow-up of patients with nonlym° phocytic leukemia. II. Acute nonlymphocytic leukemia. Cancer Genet Cytogenet 3:109124. 17. Mitelman F (1983): Catalogue of chromosome aberrations in cancer. Cytogenetics Cell Genetics 36:1-516. 18. Fitzgerald PH, Morris CM, Fraser GJ, Giles LM, Homer JW, Heaton DC, Beard MEJ (1983): Nonrandom cytogenetic changes in New Zealand patients with acute myeloid leukemia. Cancer Genet Cytogenet 8:51-66. 19. Larson RA, LeBeau MM, Vardiman JW, Testa JR, Golomb HM, Rowley JD (1983): The predictive value of initial cytogenetic studies in 148 adults with acute nonlymphocytic leukemia: A 12-year study (1970-1982). Cancer Genet Cytogenet 10:219-236. 20. ¥unis JJ (1984): Recurrent chromosomal defects are found in most patients with acute nonlymphocytic leukemia. Cancer Genet Cytogenet 11:125-137. 21. Bernstein R, Macdougall LG, 1 Pinto MR (1984): Chromosome patterns in 26 South African children with acute nonlymphocytic leukemia (ANLL). Cancer Genet Cytogenet 11:199-214. 22. Ohyashiki K (1984): Nonrandom cytogenetic changes in human acute leukemia and their clinical implications. Cancer Genet Cytogenet 11:453-471. 23. Philip P, Krogh-Jensen M, Killmann SA, Drivsholm A, Hansen NE (1978): Chromosomal banding patterns in 88 cases of acute nonlymphocytic leukemia. Leukemia Res 2:201-212. 24. Mamaeva SE, Mamaeva NN, Jartseva NM, Belaeva LV, Scherbakova EG (1983): Complete or partial trisomy for the long arm of chromosome 1 in patients with various hematologic malignancies. Hum Genet 63:107-112. 25. Dewald GW, Pierre RV, Phyliky RL (1982): Three patients with structurally abnormal X chromosomes, each with Xq13 breakpoints and a history of idiopathic acquired sideroblastic anemia. Blood 59:100-105. 26. Petit P, Fryns JP, Masure R, Van Den Berghe H (1982): Isodicentric (X)(q13): A new characteristic chromosomal anomaly in myeloproliferative syndrome? Cancer Genet Cytogenet 7:339-341. 27. Dewald GW (1984): (personal communication) 28. Berger R, Bernheim A, Daniel M-T, Valensi F, Flandrin G (1981): t(15;17) translocation in acute promyelocytic leukemia (M3) and cytological "M3 variant." Nouv Rev Fr Haematol 23:27-38. 29. Fourth International Workshop on Chromosomes in Leukemia, 1982 (1984): Chromosomes in acute promyelocytic leukemia. Cancer Genet Cytogenet 11:288-293. 30. Mitelman F, Nilsson PG, Brandt L, Alimena G, Gastaldi R, Dallapiccola B (1981): Chromosome pattern, occupation, and clinical features in patients with acute nonlymphocytic leukemia. Cancer Genet Cytogenet 4:197-214. 31. LeBeau MM, Rowley JD ~1984~: Heritable fragile sites in cancer. Nature 308:607-608.
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32. Yunis JJ (1984): Fragile sites and predisposition to leukemia and lymphoma. Cancer Genet Cytogenet 12:85-88. 33. Yunis JJ (1983): The chromosomal basis of h u m a n neoplasia. Science 221:227-236. 34. Rowley JD (1983): Human oncngene locations and chromosome aberrations. Nature 301:290-291. 35. O'Brien SJ, Nash WG, Goodwin JL, Lowy DR, Chang EH (1983): Dispersion of the ras family of transforming genes to four different chromosomes in man. Nature 302:839-842. 36. Testa JR, Mintz U, Rowley JD, Baron JM (1981): Multiple cytogenetically abnormal clones in two polycythemia vera patients. Hum Genet 57:165-168. 37. Vermaelen K, Barbieri D, Michaux JL, Tricot G, Casteels-Van Daele M, Noens L, Van Hove W, Drochmans A, Louwagie A, Van Den Berghe H (1983): Anomalies of the long arm of chromosome 11 in h u m a n myelo and lymphoproliferative disorders. I. Acute nonlymphocytic leukemia. Cancer Genet Cytogenet 10:105-116.
ABSTRACT: Unusual cytogenetic findings were noted in the leukemic cells from a patient with congenital acute monocytic leukemia (AMol or M5, according to the FAB classification), whereas, the chromosomes of cultured skin fibroblasts were normal. G-banded karyotypes of leukemic cells showed an X-autosome translocation, 46,X,t(X;lO)(Xpter-~q13::10q11.2--,qter)(10pter--~ q11.2::Xq28-*q13::Xq28--~qter). Review of reported cases of acute nonlymphocytic leukemia (ANLL) with rearrangements involving chromosomes #10 or X showed a high frequency of abnormalities of the short arm of #10 in myelomonocytic (M4) and monocytic (M5) leukerajas, particularly in patients less than 2-yr-of-age. Although previously reported cases of ANLL in infants are predominantly of these types, the translocation observed in this case is unique. Fragile sites known to exist on chromosomes #10 and X are not associated with neoplasia and, except for Xq27-28, were not at the breakpoints of the case presented. The precise location of a human cellular oncogene recently identified on the X chromosome remains unknown.
INTRODUCTION Among the types of leukemia that are associated with specific chromosomal changes, acute monocytic leukemia (AMoL or M5, according to the FAB classification [1]) has been found to involve (in a large n u m b e r of cases) rearrangements of the long arm of chromosome #11, most frequently at b a n d 11q23 [2-4]. X-autosome translocations in association with leukemias or other neoplastic diseases are very u n c o m m o n [5]. We present a G-banded chromosome study of leukemic cells with a translocation involving chromosomes # 1 0 and X from a n e w b o r n infant with skin lesions, hepatosplenomegaly, and high n u m b e r s of circulating immature cells. The patient was diagnosed as having AMoL (M5) on the basis of morphologic and cytochemical examination of peripheral blood smears. CASE REPORT AND CYTOGENETIC FINDINGS The infant was the 2 Kg product of a 35-wk pregnancy of a 21-yr-old American Indian mother, complicated by premature labor at 30 wk, requiring ritodrine hydro-
From the Departmentsof Pathology, Pediatrics, and Medical Genetics,OregonHealth Sciences University, Portland, OR Address requests for reprints to Dr. John Weis, Department of Pathology, Mayo Clinic/ Mayo Foundation, Rochester, MN 55905. Received June 16, 1984; accepted July 30, 1984.
357 © 1985 ElsevierScience PublishingCo., Inc. 52 VanderbiltAve., New York, NY 10017
Cancer Geneticsand Cytogenetics16, 357-364 (1985) 0165-4608/85/$03.30
358
J. Weis et al. chloride until vaginal delivery at 35 wk. There was no maternal exposure to radiation, toxins, infections, or medications--other than ritodrine--during the pregnancy. The mother was gravida 4, para 4, and the three older siblings of the patient were normal. The infant required immediate resuscitation, and was noted to have multiple flat white and nodular skin lesions, and hepatosplenomegaly. On admission, hemoglobin was 11.4 g/dl, platelet count 15,000/ram 3, and WBC count 200,000/ mm 3. Artificial ventilation and blood pressure support with dopamine and dobutamine were required, and a double-volume exchange transfusion was performed for hyperviscosity and anemia. Examination of the infant's Wright-stained peripheral blood smear revealed more than 95% of the nucleated cells to be immature cells with large, often folded or lobulated nuclei. The leukemic cells had abundant cytoplasm with fine azurophilic granulation, and often contained multiple clear vacuoles (Fig. 1). Cytochemical studies included myeloperoxidase, Sudan black, naphthol-ASD-chloroacetate esterase (NASDCA), and alpha-naphthyl-butyrate esterase (ANBE). Testing for NaF inhibition of esterase activity was not done. Positivity of varying intensity was noted in approximately 10% of cells for myeloperoxidase and 50% of cells with Sudan black. Cytochemical staining for ANBE was strikingly positive in all of the leukemic cells, and the NASDCA reaction also was positive, though much more weakly staining, in essentially all of the cells. In our laboratory, significant ANBE-positive staining is restricted to monocytes, which generally are negative for NASDCA. This is also the experience of other investigators who, like us, use fast blue BB (Sigma, St. Louis) as dye coupler in this reaction [6]. In spite of the weakly positive NASDCA reaction, the neoplasm was considered to be pure monocytic (M5), subtype M5b, because of their uniformly monocytoid appearance on Wright-stained blood films. The infant died at 27-hr-of age with unremitting acidosis and cardiac failure. Postmortem examination revealed leukemic infiltration of the infant's heart, lungs, Figure I
AMol cells in Wright-stained peripheral blood smear.
t(X;10) in AMoL
359
5
C
6
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8
10
11
12
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t-13
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Figure 2 (A) Karyotype of cell from unstimulated peripheral blood with a translocation involving chromosome #10 and X. (B) Chromosome pairs #10 and X from karyotype in Fig. 2A with schematic drawing showing breakpoints and ,translocation.
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J. Weis et al. liver, spleen, kidneys, l y m p h nodes, and bone marrow. In addition, the cutaneous lesions noted on p h y s i c a l exam were shown to be nodules of leukemic cells, in some areas associated with subcutaneous fat necrosis. Cytogenetic studies were performed on the infant's u n s t i m u l a t e d p e r i p h e r a l blood and cultured skin fibroblasts. A n a m e t h o p t e r i n - s y n c h r o n i z e d 24-hr culture of peripheral blood was studied following G-banding. Twenty r a n d o m l y selected metaphases from the peripheral blood all exhibited the t(X;10) (Xpter-~q13::10q11.2--~qter)(10pter-~q11.2::Xq28--~q13::Xq28--~qter)(Fig. 2). This abnormality was not seen in 20 mitoses e x a m i n e d from the cultured skin fibroblasts, all of w h i c h were 46,XX.
DISCUSSION AMol (M5) comprises a significant p r o p o r t i o n of acute n o n l y m p h o c y t i c leukemia (ANLL) occurring in neonates and infants less than 1-yr-of-age, and frequently is associated with c h r o m o s o m a l rearrangements involving the long arm of chromosome #11, particularly band 11q23 [2-4, 7-11]. The poorly differentiated form of M5 (M5a or monoblastic) is more strongly associated with this a b n o r m a l i t y than the well differentiated form (M5b or monocytic) [3, 4, 9-11]. In a recent review by Abe et al., most of the other cases of acute leukemia in this age group are either m y e l o m o n o c y t i c or acute l y m p h o b l a s t i c l e u k e m i a (ALL), both of w h i c h also are associated with c h r o m o s o m a l rearrangements involving 11q23 [7]. Six of eight cases of ALL in infants less than 1-yr-of-age c o m p i l e d by those investigators showed t(4;11), w h i c h in four cases was 5(4;11)(q21;23). The m y e l o m o n o cytic nature of t(4;11) infantile acute l e u k e m i a recently has been d e m o n s t r a t e d by Nagasaka et al., confirming observations first reported in 1981 by Parkin et al. [12, 13]. If t(4;11) infantile leukemia is considered to be a subgroup of m y e l o m o n o c y t i c leukemia, then 18 of the 29 cases (62%) reported by Abe et a l , are either monocytic or have a monocytic component. Rearrangements involving c h r o m o s o m e # 1 0 are m u c h less c o m m o n than chromosome #11 in ANLL, and no cases have been reported involving the vicinity of the q11.2 breakpoint in our case. Review of p r e v i o u s l y reported cases of chromosome #10 rearrangements in ANLL show involvement of the short arm in a high percentage of cases, particularly in monocytic (M5) and m y e l o m o n o c y t i c (M4) types of ANLL [11, 14-22]. Although not present in our case, 18 of the 32 reported cases of ANLL with translocations, insertions, or deletions of c h r o m o s o m e # 1 0 with identifiable breakpoints involved the short arm. Of 16 cases of M4 or M5 types of ANLL with c h r o m o s o m e #10 rearrangements and identifiable breakpoints, 12 (75%) had a breakpoint in this region, including all seven cases in patients less than 2-yr-of-age. These data are listed in Table 1. If only M5 classifications are considered, nine of 11 cases showed a rearrangement involving the p11-p15 region. Although our case is an exception, the consistency of this abnormality among other cases with c h r o m o s o m e #10 rearrangements, particularly among cases of M4 and M5 types of ANLL, may be significant. Rearrangements of the X c h r o m o s o m e involving the q13 breakpoint observed in our case have been reported in three cases of ANLL and one case of acute leukemia, not specified as to l y m p h o c y t i c or n o n l y m p h o c y t i c type. Two cases of ANLL not s u b t y p e d as to FAB classification involved the t(X;9)(9qter-~9q32::Xq13-->Xqter) and dic(X;X)(Xpter-~Xq13::Xq13-->Xpter) [23]. Del(X)(q11) was observed in one case of M4 ANLL, and t(X;1)(q13;p12) in one case of acute leukemia, otherwise not specified [23, 24]. Chromosomal abnormalities involving breakpoints have been reported in four cases of m y e l o d y s p l a s t i c syndromes, and an additional case has been identified by
4/mo 6/mo
12/mo 15/mo 37 86
9 6O 2 12/too 10/mo 21/mo 66 16 37
NG °
1 2
3 4 5 6
7 8 9 10 11 12 13 14 15
16
NG
F M F M M F M F F
M F F M
F F
Sex
M5a
M5 M4 M4 M4 M5a M5a M5a M5a M5
M4 M4 M5 M5
M5 M5
FAB
bCase referenced in this review article.
QNG,Not given.
Age
10 s t r u c t u r a l a b n o r m a l i t i e s Karyotype
46,XY,del(lO)(p12),del(11)(q23),der(8),ins(1o)(p12) 46,XY,t(1;9)(q11;q34),t(1o;11)(p14;q14) 46,XY,t(6;10;11)(p22;p14;q14) 47,XX, + 8,t(10;11)(p13;q14) 57-58,XX,+1,+1,+3,-4,-5,+6,+6,-8,+ 11,+12,-17,+19,-20,del(1o)(q24?),+8 to 4acen? frag t(1o;11)(p14;q13)
46,XY / 46,XY,t(10;11)(p14 ;q13 )
44,XY,t(3;5)(qter;q13),t(7;12)(q12;14),t(7;10)(q12;q21),- 8 , - 1 7 , - 1 8 , - 20 46,XX,t(5;10)(q35;q23)
46,XX,t( lO;11){p15;q2273?)
or 9 i n a r , + 1
46,XX,dir ins(10;11)(p11;q23q24?)/54,XX, + 4, + 8, + 12 + 16, + 19, + 20,dir ins(10;11) 51 ,XX, + 3, + 6, + 9, + 19, - 10,del(1)(p22), + del(1)(p22),dup(11)(qllq21), + der(10)t(10;?)(p13 ;?)/ 52,XX,same, + 18 46,XY/46,XY,t(10,11)(p14;q13) 46,XX,t(10;11)(p15;q21) 54,XX, + 1, + 1, + 3, + 6, + 6, + 11, + 12, - 4, - 5, - 8, - 20,del(10)(q24?), + 5mar, + 4ace 46,X,del(Y)(q12), + 2,der(2)t(2;14)(p11.2;q11.2), + iso5p, + 8,t(9;10)(q13;p11.2),del(9)(pterq13),del(10)(p11.2pter),- 1 3 , - 14
M4/M5 ANLL Cases with chromosome
Patient
Table 1
lO
21 30 14 15 11 11 11 11 36
15 37 b 19 20
14 14
Reference
O3 C3~
362
1. Weis et al.
the Mayo Clinic investigators subsequent to the publication of their report [25-27]. Four of the cases were idiopathic acquired sideroblastic anemias (IASA), one of which progressed to ANLL, M1 subtype. Four of these five cases had isodicentric X chromosomes, and Dewald et al. suggest that the case described by Philips et al. as dic (x;X)(Xpter--~Xq13::Xq13-~Xpter) is probably also an isodicentric X chromosome rather than a translocation dicentric X chromosome, because of the presence of a normal X chromosome in the same karyotype (23, 25-27). Two cases of ANLL with chromosomal rearrangements involving the Xq28 breakpoint seen in our case have been reported, both of which were FAB type M3. In one case t(X;9)(q28;q22) was present in addition to t(15;17) in the leukemic cells [28]. The other case had two separate malignant clones, one with t(15;17) and the other with t(X;7)(q28;q21) [29]. One other case of ANLL, FAB type M1 or M2, had leukemic cells with the karyotype 46, X, del(X)(q21), t(5;21)(q13;q22) [30]. In this case, the deletion might have been at the q13 band rather than q21. Recent reports have suggested that the presence of a heritable fragile site may predispose an i n d i v i d u a l with that fragile site to the development of a n e o p l a s m associated with chromosomal rearrangements involving that site [31-33]. Seven of ten patients studied with a subgroup of myelomonocytic leukemia (M4) with bone marrow eosinophilia, whose leukemic cells showed an inversion or deletion of chromosome #16 at band q22 were shown to have a fragile site at this band in their normal cells [31]. Fragile sites at 11q23 in cells from a patient with t(11;14)(q13;q32) small cell l y m p h o m a and at 12q13 in a patient with t(12;14)(q13;q32) l y m p h o m a have also been described [33]. Fragile sites k n o w n to exist on chromosome #10 (at q23.3 and q25.2) and on X (at q27-28) are not associated with neoplastic disease. Although h u m a n cellular oncogenes have been identified at breakpoints involved in chromosomal aberrations associated with several neoplasms [34], n o n e has yet been found on chromosome #10. Recently, a member of the ras family of oncogenes, c-Ha-ras-2, has been assigned to the X chromosome [35]. The question of whether or not the abnormality observed in our case may involve c-Ha-ras-2 must await clarification of this gene's position on the X chromosome.
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