Complex Ph Translocations in Chronic Myeloid Leukemia
Chromosome translocations are c o m m o n l y found in clones of cells from all types of h u m a n leukemia. They take the form of simple translocations involving rearrangement of two chromosomes and c o m p l e x translocations derived from rearrangement of more than two chromosomes. Complex translocations have attracted m u c h attention as variant forms of the simple t(9;22)(q34;q11) w h i c h characterizes chronic m y e l o i d leukemia (CML), some forms of acute l y m p h a t i c leukemia, and other P h i l a d e l p h i a (Ph) c h r o m o s o m e leukemias. Variant Ph translocations u s u a l l y involve either c h r o m o s o m e 22 and another c h r o m o s o m e apart from c h r o m o s o m e 9 (simple Ph variants) or one or more chromosomes in a d d i t i o n to c h r o m o s o m e s 9 and 22 (complex Ph variants). The characteristic Ph c h r o m o s o m e may be masked in some c o m p l e x variants because of attachment of material from another chromosome. All Ph variants can be considered c o m p l e x translocations because molecular genetic investigation of the s u p p o s e d l y simple variants shows them to involve at least three c h r o m o s o m e s and always chromosomes 9 and 22 [1-3]. All h u m a n chromosomes except the Y chromosome have been involved in c o m p l e x translocations, but i n v o l v e m e n t is nonrandom, with marked clustering of breakpoints to regions of chromosomes 3, 11, 12, 14, and 17 [4, 5]. Variant Ph translocations were recorded in 327 cases of CML [5, 6], and several more variants have since been reported. The large number of cases raises the question of whether c o m p l e x translocations occur more c o m m o n l y in CML than do c o m p l e x interchanges related to the specific c h r o m o s o m e changes of other leukemias. That i m p r e s s i o n is certainly obtained from the Catalog of Chromosome Aberrations in Cancer [6]. The Catalog lists 308 cases with aberrant (variant) translocations, i.e., 24.2% of all 1,272 cases of Ph-positive CML recorded. In comparison, the Catalog lists complex translocations in a p p r o x i m a t e l y 4.6% of 323 cases of acute m y e l o i d l e u k e m i a (AML) that have t/8;21) and 1.5% of 120 cases of AML that have t(15;17). These figures suggest that c o m p l e x translocations are a particular feature of CML, but the Catalog is c o m p i l e d mostly from p u b l i s h e d sources and these, particularly in more recent years, are probably biased toward reports of variant translocations in CML. The First International Workshop on Chromosomes in Leukemia held in 1977 reported that 8% of 223 Ph-positive CML patients had variant translocations [7]. A more reliable indication may be obtained from p u b l i s h e d series of Ph-positive CML patients derived from single centers or areas [1, 4, 8-15]. The variants ranged in different studies from 2.9 to 8.0% of all cases of CML. In all, 92 variants were described in 1,709 cases (5.4%). I have omitted cases of Ph-negative CML from these data because of the difficulty in diagnosing that condition accurately [16]. A correction for the rare c o m p l e x c h r o m o s o m e rearrangements w h i c h show normal karyotypes [17-20] w o u l d change this estimate only marginally. Complex variants in M2 and M3 AML described in. p u b l i s h e d reports may not reflect their true incidence, in particular in c o m p a r i s o n with the attention paid to c o m p l e x variants of CML. The incidence of c o m p l e x translocations in CML is probably not significantly different from that in other forms of h u m a n leukemia.
129 © 1991 Elsevier Science Publishing Co.. Inc. 655 Avenue of the Americas. New York. NY 10010
Cancer Genet Cytogenet 55:129 131 (1991) 0165-4608/91/$03.50
130
P.H.
PETER H. F I T Z G E R A L D
Fitzgerald
Cytogenetic & Molecular Oncology Unit C h r i s t c h u r c h S c h o o l of M e d i c i n e and Christchurch Hospital Christchurch, New Zealand
REFERENCES 1. Hagemeijer A, Bartram CR, Smith EME, van Agthoven AJ, Bootsma D (1984): Is the chromosomal region 9q34 always involved in the variants of the Ph translocation? Cancer Genet Cytogenet 13:1-16. 2. Hagemeijer A, de Klein A, Godde-Salz E, Turc-Carel C, Smith EME, van Agthoven AJ, Grosveld GC (1985): Translocation of c-abl to "masked" Ph in chronic myeloid leukemia~ Cancer Genet Cytogenet 18:95-104. 3. Morris CM, Rosman I, Archer SA, Cochrane JM, Fitzgerald PH (1988): A cytogenetic and molecular analysis of five variant Philadelphia translocations in chronic myeloid leukemia. Cancer Genet Cytogenet 35:179-197. 4. Heim S, Billstrom R, Kristoffersson U, Mandahl N, Strombeck B, Mitelman F (1985): Variant Ph translocations in chronic myeloid leukemia. Cancer Genet Cytogenet 18:215-227. 5. De Braekeleer M (1987): Variant Philadelphia translocations in chronic myeloid leukemia. Cytogenet Cell Genet 44:215-222. 6. Mitelman F (1988): Catalog of Chromosome Aberrations in Cancer, 3rd ed. Alan R. Liss, New York. 7. First International Workshop on Chromosomes in Leukemia 1977 (1978): Cancer Res 38:867-868. 8. Hagemeijer A, Kroeze AFS, Abels J (1980): Cytogenetic follow-up of patients with nonlymphocytic leukemia. I. Philadelphia chromosome-positive chronic myeloid leukemia. Cancer Genet Cytogenet 2:317-326. 9. Lessard M, Le Prise P-Y (1982): Cytogenetic studies in 56 cases with Phi-positive hematologic disorders. Cancer Genet Cytogenet 5:37-49. 10. Oshimura M, Ohyashiki K, Terada H, Takaku F, Tonomura A (1982): Variant Ph 1 translocations in CML and their incidence, including two cases with sequential lymphoid and myeloid crises. Cancer Genet Cytogenet 5:187-201. 11. Ishihara T, Sasaki M, Oshimura M, Kamada N, Yamada K, Okada M, Sakurai M, Sugiyama T, Shiraishi Y, Kohno S (1983): A summary of cytogenetic studies on 534 cases of chronic myelocytic leukemia in Japan. Cancer Genet Cytogenet 9:81-92. 12. Bernstein R, Pinto MR, Wallace C, Penfold G, Mendelow B (1984): The incidence, type, and subsequent evolution of 14 variant Ph I translocations in 180 South African patients with Phi-positive chronic myeloid leukemia. Cancer Genet Cytogenet 12:225-238. 13. Groupe Fran§ais de Cytog6n~tique H~matologique (1985): Unusual Ph translocations in the French prospective study on chronic myeloid leukemia. Cancer Genet Cytogenet 16:305-309. 14. lshihara T, Minamihisamatsu M (1988): The Philadelphia chromosome. Considerations based on studies of variant Ph translocations. Cancer Genet Cytogenet 32:75-92. 15. Hild F, Fonatsch C (1990): Cytogenetic peculiarities in chronic myelogenous leukemia. Cancer Genet Cytogenet 47:197-217. 16. Fitzgerald PH, Beard MEJ, Morris CM, Heaton DC, Reeve AE (1987): Ph-Negative chronic myeloid leukaemia. Br J Haematol 66:311-314. 17. van der Plas DC, Hermans ABC, Soekarman D, Smith EME, de Klein A, Smadja N, Alimena G, Goudsmit R, Grozveld G, Hagemeijer A (1989): Cytogenetic and molecular analysis in Philadelphia negative CML. Blood 73:1038-1044. 18. Inazawa J, Nishigaki H, Takahira H, Nichimura J, Horiike S, Taniwaki M, Misawa S, Abe "1 (1989): Rejoining between 9 q * and Philadelphia chromosomes results in normal-looking chromosomes 9 and 22 in phi-negative chronic myelocytic leukemia. Hum Genet 83:115-118.
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19. Morris CM, Heisterkamp N, Kennedy MA, Fitzgerald PH, Groffen J (1990): Ph-negative chronic myeloid leukemia: Molecular analysis of ABL insertion into M-BCR on chromosome 22. Blood 76:1812-1818. 20. Morris C, Kennedy M, Heisterkamp N, Columbano-Green L, Romeril K, Groffen J, Fitzgerald P (1991): A complex chromosome rearrangement forms the BCR°ABL fusion gene in leukemic cells with a normal karyotype. Genes Chrom Cancer (in press).
Chromosome translocations are c o m m o n l y found in clones of cells from all types of h u m a n leukemia. They take the form of simple translocations involving rearrangement of two chromosomes and c o m p l e x translocations derived from rearrangement of more than two chromosomes. Complex translocations have attracted m u c h attention as variant forms of the simple t(9;22)(q34;q11) w h i c h characterizes chronic m y e l o i d leukemia (CML), some forms of acute l y m p h a t i c leukemia, and other P h i l a d e l p h i a (Ph) c h r o m o s o m e leukemias. Variant Ph translocations u s u a l l y involve either c h r o m o s o m e 22 and another c h r o m o s o m e apart from c h r o m o s o m e 9 (simple Ph variants) or one or more chromosomes in a d d i t i o n to c h r o m o s o m e s 9 and 22 (complex Ph variants). The characteristic Ph c h r o m o s o m e may be masked in some c o m p l e x variants because of attachment of material from another chromosome. All Ph variants can be considered c o m p l e x translocations because molecular genetic investigation of the s u p p o s e d l y simple variants shows them to involve at least three c h r o m o s o m e s and always chromosomes 9 and 22 [1-3]. All h u m a n chromosomes except the Y chromosome have been involved in c o m p l e x translocations, but i n v o l v e m e n t is nonrandom, with marked clustering of breakpoints to regions of chromosomes 3, 11, 12, 14, and 17 [4, 5]. Variant Ph translocations were recorded in 327 cases of CML [5, 6], and several more variants have since been reported. The large number of cases raises the question of whether c o m p l e x translocations occur more c o m m o n l y in CML than do c o m p l e x interchanges related to the specific c h r o m o s o m e changes of other leukemias. That i m p r e s s i o n is certainly obtained from the Catalog of Chromosome Aberrations in Cancer [6]. The Catalog lists 308 cases with aberrant (variant) translocations, i.e., 24.2% of all 1,272 cases of Ph-positive CML recorded. In comparison, the Catalog lists complex translocations in a p p r o x i m a t e l y 4.6% of 323 cases of acute m y e l o i d l e u k e m i a (AML) that have t/8;21) and 1.5% of 120 cases of AML that have t(15;17). These figures suggest that c o m p l e x translocations are a particular feature of CML, but the Catalog is c o m p i l e d mostly from p u b l i s h e d sources and these, particularly in more recent years, are probably biased toward reports of variant translocations in CML. The First International Workshop on Chromosomes in Leukemia held in 1977 reported that 8% of 223 Ph-positive CML patients had variant translocations [7]. A more reliable indication may be obtained from p u b l i s h e d series of Ph-positive CML patients derived from single centers or areas [1, 4, 8-15]. The variants ranged in different studies from 2.9 to 8.0% of all cases of CML. In all, 92 variants were described in 1,709 cases (5.4%). I have omitted cases of Ph-negative CML from these data because of the difficulty in diagnosing that condition accurately [16]. A correction for the rare c o m p l e x c h r o m o s o m e rearrangements w h i c h show normal karyotypes [17-20] w o u l d change this estimate only marginally. Complex variants in M2 and M3 AML described in. p u b l i s h e d reports may not reflect their true incidence, in particular in c o m p a r i s o n with the attention paid to c o m p l e x variants of CML. The incidence of c o m p l e x translocations in CML is probably not significantly different from that in other forms of h u m a n leukemia.
129 © 1991 Elsevier Science Publishing Co.. Inc. 655 Avenue of the Americas. New York. NY 10010
Cancer Genet Cytogenet 55:129 131 (1991) 0165-4608/91/$03.50
130
P.H.
PETER H. F I T Z G E R A L D
Fitzgerald
Cytogenetic & Molecular Oncology Unit C h r i s t c h u r c h S c h o o l of M e d i c i n e and Christchurch Hospital Christchurch, New Zealand
REFERENCES 1. Hagemeijer A, Bartram CR, Smith EME, van Agthoven AJ, Bootsma D (1984): Is the chromosomal region 9q34 always involved in the variants of the Ph translocation? Cancer Genet Cytogenet 13:1-16. 2. Hagemeijer A, de Klein A, Godde-Salz E, Turc-Carel C, Smith EME, van Agthoven AJ, Grosveld GC (1985): Translocation of c-abl to "masked" Ph in chronic myeloid leukemia~ Cancer Genet Cytogenet 18:95-104. 3. Morris CM, Rosman I, Archer SA, Cochrane JM, Fitzgerald PH (1988): A cytogenetic and molecular analysis of five variant Philadelphia translocations in chronic myeloid leukemia. Cancer Genet Cytogenet 35:179-197. 4. Heim S, Billstrom R, Kristoffersson U, Mandahl N, Strombeck B, Mitelman F (1985): Variant Ph translocations in chronic myeloid leukemia. Cancer Genet Cytogenet 18:215-227. 5. De Braekeleer M (1987): Variant Philadelphia translocations in chronic myeloid leukemia. Cytogenet Cell Genet 44:215-222. 6. Mitelman F (1988): Catalog of Chromosome Aberrations in Cancer, 3rd ed. Alan R. Liss, New York. 7. First International Workshop on Chromosomes in Leukemia 1977 (1978): Cancer Res 38:867-868. 8. Hagemeijer A, Kroeze AFS, Abels J (1980): Cytogenetic follow-up of patients with nonlymphocytic leukemia. I. Philadelphia chromosome-positive chronic myeloid leukemia. Cancer Genet Cytogenet 2:317-326. 9. Lessard M, Le Prise P-Y (1982): Cytogenetic studies in 56 cases with Phi-positive hematologic disorders. Cancer Genet Cytogenet 5:37-49. 10. Oshimura M, Ohyashiki K, Terada H, Takaku F, Tonomura A (1982): Variant Ph 1 translocations in CML and their incidence, including two cases with sequential lymphoid and myeloid crises. Cancer Genet Cytogenet 5:187-201. 11. Ishihara T, Sasaki M, Oshimura M, Kamada N, Yamada K, Okada M, Sakurai M, Sugiyama T, Shiraishi Y, Kohno S (1983): A summary of cytogenetic studies on 534 cases of chronic myelocytic leukemia in Japan. Cancer Genet Cytogenet 9:81-92. 12. Bernstein R, Pinto MR, Wallace C, Penfold G, Mendelow B (1984): The incidence, type, and subsequent evolution of 14 variant Ph I translocations in 180 South African patients with Phi-positive chronic myeloid leukemia. Cancer Genet Cytogenet 12:225-238. 13. Groupe Fran§ais de Cytog6n~tique H~matologique (1985): Unusual Ph translocations in the French prospective study on chronic myeloid leukemia. Cancer Genet Cytogenet 16:305-309. 14. lshihara T, Minamihisamatsu M (1988): The Philadelphia chromosome. Considerations based on studies of variant Ph translocations. Cancer Genet Cytogenet 32:75-92. 15. Hild F, Fonatsch C (1990): Cytogenetic peculiarities in chronic myelogenous leukemia. Cancer Genet Cytogenet 47:197-217. 16. Fitzgerald PH, Beard MEJ, Morris CM, Heaton DC, Reeve AE (1987): Ph-Negative chronic myeloid leukaemia. Br J Haematol 66:311-314. 17. van der Plas DC, Hermans ABC, Soekarman D, Smith EME, de Klein A, Smadja N, Alimena G, Goudsmit R, Grozveld G, Hagemeijer A (1989): Cytogenetic and molecular analysis in Philadelphia negative CML. Blood 73:1038-1044. 18. Inazawa J, Nishigaki H, Takahira H, Nichimura J, Horiike S, Taniwaki M, Misawa S, Abe "1 (1989): Rejoining between 9 q * and Philadelphia chromosomes results in normal-looking chromosomes 9 and 22 in phi-negative chronic myelocytic leukemia. Hum Genet 83:115-118.
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19. Morris CM, Heisterkamp N, Kennedy MA, Fitzgerald PH, Groffen J (1990): Ph-negative chronic myeloid leukemia: Molecular analysis of ABL insertion into M-BCR on chromosome 22. Blood 76:1812-1818. 20. Morris C, Kennedy M, Heisterkamp N, Columbano-Green L, Romeril K, Groffen J, Fitzgerald P (1991): A complex chromosome rearrangement forms the BCR°ABL fusion gene in leukemic cells with a normal karyotype. Genes Chrom Cancer (in press).
