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Translocation (8;21)(q22;q22) and the myelodysplastic syndrome
Lr,rkrmru
Pergamon
Re\rarch Vol 19, No. Y, pp. h75-h77, 1995. Cupvrleht 0 1995 Ekevicr Scmce Ltd Printed in &eat Britain. All rights mewed 0145%212h/Y5 $9.50 + 0.00
0145-2126(95)00055-O
LETTER TO THE EDITORS TRANSLOCATION
(8;21)(q22;q22) AND THE MYELODYSPLASTIC SYNDROME
In a recent commentary on a report of a case of oligoblastic leukemia with t(8;21)(q22;q22) [l], Hamblin doubted that t(8;21) could occur in the myelodysplastic syndromes (MDS) [2]. He commented that when t(8;21) occurred in cases that would be classified morphologically as MDS according to the FrenchAmerican-British Cooperative Group (FAB) criteria [3], the clinical course would resemble that of acute myeloid leukemia (AML) with t(8;21). On these grounds, Hamblin contended that the diagnosis should be AML, and that the MDS features should be regarded as part of the leukemia. From a clinical perspective, Hamblin was certainly right in pointing out that for cases with t(8;21), it is probably a matter of semantics whether the diagnosis should be AML or MDS, as accumulation of blasts to the leukemic range (>30%) would invariably occur, and these cases should be treated as for AML. This has been observed in most reports of MDS with t(8;21) [4-81, as well as according to our own experience [9, lo]. From a pathological perspective, however, we suggest that there may still be a place for retaining the occasional diagnosis of MDS in cases with t(8;21). The FAB classification criteria [3, 111 are well accepted as the standard for the diagnosis of MDS and AML, and are well known to both hematopathologists and clinicians. When a patient presents initially, the hematopathologist will have to make a diagnosis based on morphology and cytochemistry without the foresight of cytogenetics. If the blast count is less than 30%, and myelodysplastic features are present, the diagnosis will have to be one of MDS. When cytogenetic analysis shows t(8;21) (which in the best of centers will take at least 3 days), the hematopathologist still cannot change the diagnosis without creating a new classification scheme of his own, and confusing his clinical colleagues. However, what is imperative is that he needs to inform the clinicians that the patient should receive antileukemic therapy, as the natural course of the disease will resemble that of AR4L.
Practical considerations aside, there may be biological reasons why the diagnosis of MDS in t(8;21) could be retained. Implicit in the diagnosis of MDS is that it is a trilineage disorder involving a multipotential myeloid stem cell [12]. Such is not implied in the diagnosis of AML, although some may well be the case. The pathological significance, therefore, of making a diagnosis of MDS in t(8;21) is that the case could be a trilineage disorder. Hence, may t(8;21) involve a multipotential myeloid cell? There is increasing evidence to suggest that indeed it may. Firstly, dysplastic features in the myeloid series, including pseudo Pelger-Htiet nuclear anomaly and hypogranularity, occur in t(8;21) but are usually considered part of the leukemia [13]. However, the presence of dyserythropoietic features, including maturation asynchrony, binucleation and megaloblastoid changes have also been observed [14]. In addition, marrow eosinophilia (>5%) occurred in about 20% of the cases [9, 131. These eosinophils possessed abnormal granules and occasionally Auer rods [13], showing that they belonged to the mutated clone. Although initially thought to involve mainly the granulocytic series, t(8;21) has now been shown in leukemia of myelomonocytic lineage [9, 1.5-171. Furthermore, trilineage dysplasia has been well documented in the few cases of MDS with t(8;21) [6,9, 171. These suggest that the target cell involved in t(8;21) may be capable at least of granulocytic, monocytic, eosinophilic and possibly erythroid differentiation. Secondly, it is now known that t(8;21) results in fusion of the AMLl gene on 21q22 [18] to the ET0 gene on 8q22 [19], generating a chimeric AMLl/ETO transcript which can be detected by reverse transcription polymerase chain reaction (RT-PCR) [20]. This assay has a sensitivity of 10ph. Using the highly sensitive RT-PCR, several groups found that AMLl/ETO was still demonstrable in patients with t(8;21) who were in longterm hematologic remission [lo, 21-231. Although this raises interesting issues about the biological role AMLI/ ET0 plays in leukemogenesis [23], there is no doubt that the mutated clone is still present, albeit in a very small size, for as long as up to 8 years in remission [22]. Hence, the t(8;21) clone must be capable of continuous self renewal in order to persist for such long periods. It
Correspondence to: Dr Y. L. Kwong, University Department of Medicine, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong (Tel: 852 2 855 4776; Fax: 852 2
872 5828). 675
Letter to the Editors
h7b
has been envisaged that only leukemias arising from stem cells are capable of such continuous self renewal [24], and they are incurable by chemotherapy because of this extensive self replication. However, leukemias occurring in relatively committed progenitor cells have a finite capability of self renewal, and so are potentially curable [24]. t(8;21) would fit the former model, as the mutated clone appears to persist and is not ‘curable’ by chemotherapy, although why it remains subclinical during remission still needs to be defined. In contrast, a good example of the latter mode! is acute promyelocytic leukemia (APL) with the characteristic t(15;17)(q24;q21), which involves the granulocytic lineage. t(15;17)(q24;q21) results in the generation of a chimeric PML/RARx transcript [25]. In APL patients in long-term hematologic remission, PML/RARr is, in contrast to AMLIIETO, consistently not demonstrable [25], showing that eradication of the clone may have occurred. Finally, t(8;21) has been reported in about 40 cases of therapy-related AML, after the use of alkylating agents, radiotherapy or topoisomerase II inhibitors [lo, 26-301. In about 13% of these cases [27,29,30], an antecedent MDS was documented. In two cases [29, 301, t(8;21) was actually found at the MDS phase, with 2% and 10% of blasts in the marrow, respectively. These reports argue for the fact that t(8;21) might progress through an MDS before the onset of overt leukemia. Therefore, it appears that, at least in some cases, t&21) may involve a multipotential myeloid cell. The diagnosis of MDS in a case of t(8;21), when called for occasionally on histologic grounds, is thus also conceptually viable. However, management of these patients is always governed by the known clinical course of t(8;21) rather than by the particular diagnosis. Obviously, more clinical and scientific data are needed to delineate the biological characteristics of t(8;21), as well as its role in leukemogenesis. One way of examining this is to fractionate hematopoietic cells of different lineages, and to look for AMLIJETO as a marker of the mutated clone. Finally, benefits will no doubt be derived from careful observation and classification according to criteria currently available. Only then will it be known whether an exception in the current classification system is needed, or whether the diagnosis of MDS is justifiable, in myeloid disorders with t(8;21). References 1. Xue Y., Yu F., Zhou Z., Cue Y., Xie X. & Lin B. (1994) Translocation (8;21) in oligoblastic leukemia: is this a true myelodysplastic syndrome?Leukemia Rex 18, 761. 2, Hamblin T. J. (1994) Pseudo-myelodysplasticsyndrome with t&21). LeukemiaRes. 18, 767. 3. Bennett J. M., Catovsky D., Daniel M. T., Flandrin G.,
Galton D. A. G., Gralnick H. R. & Sultan C. (1982) The French-American-British Co-operative Group: proposals for the classification of the myelodysplasticsyndromes.Br. J. Haematol. 51, 189. 4. Gold E. J., Conjalka M., Pelus L. M., Jhanwar S. C.,
Broxmeyer H., Millcdton A. B., Clarkson B. D. & Moore M. A. S. (1983) Marrow cytogenetic and cell culture analyses of the myelodysplastic syndromes. Insights to pathophysiology and prognosis.J. clin. Oncol. 1, 627. 5. Knapp R. H., Dewald G. W. & Pierre R. V. (1985) Cytogenetic studies in 174 consecutive patients with preleukemic or myelodysplastic syndromes. Muyo Clin. Proc. 60, 507. 6. Maserati E., Casali M., Pasqulai F., Locatelli F., Gianai S.,
Prete L., Zecca M., Invernizzi R. & Bassan R. (1992) Translocation (8;21) in two casesof refractory anemiawith excess of blasts in transformation. Carzcev Genet. Cytogenet. 58, 76. 7. Estey E. H., Trujillo J. M., Cork A., O’Brien S., Beran M.,
Kantarjian H., Keating M., Freireich E. J. & Stass S. (1992) AML-associated cytogenetic abnormalities ((inv)l6, del(16), t(8;21)) in patients with myelodysplastic syndromes.Hemat. Pathol. 6, 43. 8. Sole F., Prieto F., Badia L., Woessner S., Florensa L., Caballin M. R., Coll M. D., BessesC. & Sans-SabrafenJ. (1992) Cytogenetic studies in 112 cases of untreated myelodysplastic syndromes.Cancer Genet. Cytogenet. 64, 12. 9. Kwong Y. L., Liu H. W., Ching L. M., Pollock A. & Chan
L. C. (1993) Translocation (8;21) and multilineage involvement. Am. J. Hematol. 43, 212. 10. Kwong Y. L., Chan V., Wong K. F. & Chan T. K. (1995) The use of the polymerasechain reaction in the detection of AMLl/ETO fusion transcript in t(8;21). Cancer 75,821. 11. Bennett J. M., Catovsky D., Daniel M. T., Flandrin G., Galton D. A. G., Gralnick H. R. & Sultan C. (1985) Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann. Intern. Med. 45, 285. 12. JacobsA. & Clark R. E. (1986) Pathogenesisand clinical variations in the myelodysplastic syndromes. Clin. Haematol. 15, 925. 13. Swirsky D. M., Li Y. S., Matthews J. G., Flemans R. J.,
ReesJ. K. H. & Hayhoe F. G. J. (1984) 8121translocation in acute granulocytic leukaemia: cytological, cytochemical and clinical features.Br. J. Haematol. 56, 199. 14. Trujillo H. M., Cork A., Ahearn M. J., Youness E. L. & McCredie K. B. (1979) Hematologic and cytologic characterizationof S/21 translocation in acute granulocytic leukemia. Blood 53, 695. 15. Groupe Francais de Cytogenetique Hematologique. (1990) Acute myelogenous leukemia with an 8;21 translocation. A report on 148 cases from the Groupe Franqais de CytogCnCtique Hematologique. Cancer Genet. Cytogenet. 44, 169. 16. Mitelman F. (1991) Catalogue of Chromosomal Aberrutions in Cancer, Fourth Ed, p. 575. Wiley Liss, New York. 17. Auger M. J., Ross R. M. & Mackie M. J. (1991) 8;21 translocation with duplication of the der(21) in a patient with myelomonocytic leukemia. Cancer Genet. Cytogenet. 51, 139. 18. Miyoshi H., Shimizu K., Kozu T., Maseki N., Kaneko Y. & Ohki M. (1991) t(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AMLI. Proc. natn. Acad. Sci. USA 88,10431.
Letter to the Editors 19. Erickson P., Gao J., Chang K. S., Look T., Whisenant E., Raimondi S., Lasher R., Trujillo J., Rowley J. & Drabkin H. (1992) Identification of breakpoints in t(8;21) acute myelogenous leukemia and isolation of a fusion transcript, AMLlIETO, with similarity to Drosophila segmentation gene, runt. Blood 80, 1825. 20. Nucifora G., Birn D. J., Erickson P., Gao J., LeBeau M. M., Drabkin H. A. & Rowley J. D. (1993) Detection of DNA rearrangements in the AMLl and ET0 loci and of an AMLliETO fusion mRNA in patients with t&21) acute myelogenous leukemia. Blood 81, 883. 21. Chang K. S., Fan Y. H., Stass S. A., Estey E. H., Wang G., Trujillo J. M., Erickson P. & Drabkin H. (1993) Expression of AMLl-ET0 fusion transcripts and detection of minimal residual disease in t(8;21) positive acute myeloid leukemia. Oncogr/le 8, 893. 22. Nucifora G., Larson R. A. & Rowley J. D. (1993) Persistence of the 8;21 translocation in patients with acute myeloid leukemia type M2 in long-term remission. Blood 82, 712. 23. Kusec R., Lacsika K., Knob1 P., Fried1 J., Greinix H., Kahls P., Linkesch W., Schwarzinger I., Mitterbauer G., Purtscher B., Hass 0. A., Lechner K. & Jaeger U. (1994) AMLl/ETO fusion mRNA can be detected in remission blood samples of all patients with t(8;21) acute myeloid leukemia after chemotherapy or autologous bone marrow transplantation. Leukemia 8, 735. 24. Greaves M. F. (1993) Stem cell origins of leukaemia and curability. Br. J. Cancer 67, 413. 25. Grignani F., Fagioli M., Alcalay M., Longo L., Pandolfi P.P., Donti E., Biondi A., LoCoco F., Grignani F. & Pelicci P.G. (1994) Acute promyelocytic leukemia: from genetics to treatment. Blood 83, 10.
677
26. Pedersen-Bjergaard J., Daugaard G., Hansen S. W., Philip P., Larsen S. 0. & Rorth M. (1991) Increased risk of myelodysplasia and leukaemia after etoposide, cisp’atin and bleomycin for germ cell tumours. Lancet 338, 353. 27. Quesnel B., Kantarjian H., Bjergaard J. P., Brault P., Estey E., Lai J. L., Tilly H., Stoppa A. M., Archimbaud E., Harousseau J. L., Bauters F. & Fenaux P. (1993) Therapyrelated acute myeloid leukemia with t(8;21), inv(l6), and t(8;16): a report on 25 cases and review of the literature. J. clin. Oncol. 11, 2370. 28. Pedersen-Bjergaard J., Philip P., Larsen S.O., Jensen G. & Byrsting K. (1990) Chromosome aberrations and prognostic factors in therapy-related myelodysplasia and acute nonlymphocytic leukemia. Blood 76, 1083. 29. Berger R., Hillion J., Janvier D., Chen Z. & Bussel A. (1993) t(8;21) prior to acute leukemia. Cancer Genet. Cytogenet. 70, 125. 30. Bernheim A., Duverger A., Fouquet F., Bayle C. & Oberlin 0. (1995) FISH diagnosis of t&21) in a myelodysplasia secondary to Hodgkin lymphoma. Leukemia 9, 107.
Y. L. Kwong* and K. F. Wang-F *Division of Hematology, University Department of Medicine, Queen Mary Hospital, Pokfulam Road, Hong Kong; and fDepartment of Pathology, Queen Elizabeth Hospital, Pokfulam Road, Hong Kong
Pergamon
Re\rarch Vol 19, No. Y, pp. h75-h77, 1995. Cupvrleht 0 1995 Ekevicr Scmce Ltd Printed in &eat Britain. All rights mewed 0145%212h/Y5 $9.50 + 0.00
0145-2126(95)00055-O
LETTER TO THE EDITORS TRANSLOCATION
(8;21)(q22;q22) AND THE MYELODYSPLASTIC SYNDROME
In a recent commentary on a report of a case of oligoblastic leukemia with t(8;21)(q22;q22) [l], Hamblin doubted that t(8;21) could occur in the myelodysplastic syndromes (MDS) [2]. He commented that when t(8;21) occurred in cases that would be classified morphologically as MDS according to the FrenchAmerican-British Cooperative Group (FAB) criteria [3], the clinical course would resemble that of acute myeloid leukemia (AML) with t(8;21). On these grounds, Hamblin contended that the diagnosis should be AML, and that the MDS features should be regarded as part of the leukemia. From a clinical perspective, Hamblin was certainly right in pointing out that for cases with t(8;21), it is probably a matter of semantics whether the diagnosis should be AML or MDS, as accumulation of blasts to the leukemic range (>30%) would invariably occur, and these cases should be treated as for AML. This has been observed in most reports of MDS with t(8;21) [4-81, as well as according to our own experience [9, lo]. From a pathological perspective, however, we suggest that there may still be a place for retaining the occasional diagnosis of MDS in cases with t(8;21). The FAB classification criteria [3, 111 are well accepted as the standard for the diagnosis of MDS and AML, and are well known to both hematopathologists and clinicians. When a patient presents initially, the hematopathologist will have to make a diagnosis based on morphology and cytochemistry without the foresight of cytogenetics. If the blast count is less than 30%, and myelodysplastic features are present, the diagnosis will have to be one of MDS. When cytogenetic analysis shows t(8;21) (which in the best of centers will take at least 3 days), the hematopathologist still cannot change the diagnosis without creating a new classification scheme of his own, and confusing his clinical colleagues. However, what is imperative is that he needs to inform the clinicians that the patient should receive antileukemic therapy, as the natural course of the disease will resemble that of AR4L.
Practical considerations aside, there may be biological reasons why the diagnosis of MDS in t(8;21) could be retained. Implicit in the diagnosis of MDS is that it is a trilineage disorder involving a multipotential myeloid stem cell [12]. Such is not implied in the diagnosis of AML, although some may well be the case. The pathological significance, therefore, of making a diagnosis of MDS in t(8;21) is that the case could be a trilineage disorder. Hence, may t(8;21) involve a multipotential myeloid cell? There is increasing evidence to suggest that indeed it may. Firstly, dysplastic features in the myeloid series, including pseudo Pelger-Htiet nuclear anomaly and hypogranularity, occur in t(8;21) but are usually considered part of the leukemia [13]. However, the presence of dyserythropoietic features, including maturation asynchrony, binucleation and megaloblastoid changes have also been observed [14]. In addition, marrow eosinophilia (>5%) occurred in about 20% of the cases [9, 131. These eosinophils possessed abnormal granules and occasionally Auer rods [13], showing that they belonged to the mutated clone. Although initially thought to involve mainly the granulocytic series, t(8;21) has now been shown in leukemia of myelomonocytic lineage [9, 1.5-171. Furthermore, trilineage dysplasia has been well documented in the few cases of MDS with t(8;21) [6,9, 171. These suggest that the target cell involved in t(8;21) may be capable at least of granulocytic, monocytic, eosinophilic and possibly erythroid differentiation. Secondly, it is now known that t(8;21) results in fusion of the AMLl gene on 21q22 [18] to the ET0 gene on 8q22 [19], generating a chimeric AMLl/ETO transcript which can be detected by reverse transcription polymerase chain reaction (RT-PCR) [20]. This assay has a sensitivity of 10ph. Using the highly sensitive RT-PCR, several groups found that AMLl/ETO was still demonstrable in patients with t(8;21) who were in longterm hematologic remission [lo, 21-231. Although this raises interesting issues about the biological role AMLI/ ET0 plays in leukemogenesis [23], there is no doubt that the mutated clone is still present, albeit in a very small size, for as long as up to 8 years in remission [22]. Hence, the t(8;21) clone must be capable of continuous self renewal in order to persist for such long periods. It
Correspondence to: Dr Y. L. Kwong, University Department of Medicine, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong (Tel: 852 2 855 4776; Fax: 852 2
872 5828). 675
Letter to the Editors
h7b
has been envisaged that only leukemias arising from stem cells are capable of such continuous self renewal [24], and they are incurable by chemotherapy because of this extensive self replication. However, leukemias occurring in relatively committed progenitor cells have a finite capability of self renewal, and so are potentially curable [24]. t(8;21) would fit the former model, as the mutated clone appears to persist and is not ‘curable’ by chemotherapy, although why it remains subclinical during remission still needs to be defined. In contrast, a good example of the latter mode! is acute promyelocytic leukemia (APL) with the characteristic t(15;17)(q24;q21), which involves the granulocytic lineage. t(15;17)(q24;q21) results in the generation of a chimeric PML/RARx transcript [25]. In APL patients in long-term hematologic remission, PML/RARr is, in contrast to AMLIIETO, consistently not demonstrable [25], showing that eradication of the clone may have occurred. Finally, t(8;21) has been reported in about 40 cases of therapy-related AML, after the use of alkylating agents, radiotherapy or topoisomerase II inhibitors [lo, 26-301. In about 13% of these cases [27,29,30], an antecedent MDS was documented. In two cases [29, 301, t(8;21) was actually found at the MDS phase, with 2% and 10% of blasts in the marrow, respectively. These reports argue for the fact that t(8;21) might progress through an MDS before the onset of overt leukemia. Therefore, it appears that, at least in some cases, t&21) may involve a multipotential myeloid cell. The diagnosis of MDS in a case of t(8;21), when called for occasionally on histologic grounds, is thus also conceptually viable. However, management of these patients is always governed by the known clinical course of t(8;21) rather than by the particular diagnosis. Obviously, more clinical and scientific data are needed to delineate the biological characteristics of t(8;21), as well as its role in leukemogenesis. One way of examining this is to fractionate hematopoietic cells of different lineages, and to look for AMLIJETO as a marker of the mutated clone. Finally, benefits will no doubt be derived from careful observation and classification according to criteria currently available. Only then will it be known whether an exception in the current classification system is needed, or whether the diagnosis of MDS is justifiable, in myeloid disorders with t(8;21). References 1. Xue Y., Yu F., Zhou Z., Cue Y., Xie X. & Lin B. (1994) Translocation (8;21) in oligoblastic leukemia: is this a true myelodysplastic syndrome?Leukemia Rex 18, 761. 2, Hamblin T. J. (1994) Pseudo-myelodysplasticsyndrome with t&21). LeukemiaRes. 18, 767. 3. Bennett J. M., Catovsky D., Daniel M. T., Flandrin G.,
Galton D. A. G., Gralnick H. R. & Sultan C. (1982) The French-American-British Co-operative Group: proposals for the classification of the myelodysplasticsyndromes.Br. J. Haematol. 51, 189. 4. Gold E. J., Conjalka M., Pelus L. M., Jhanwar S. C.,
Broxmeyer H., Millcdton A. B., Clarkson B. D. & Moore M. A. S. (1983) Marrow cytogenetic and cell culture analyses of the myelodysplastic syndromes. Insights to pathophysiology and prognosis.J. clin. Oncol. 1, 627. 5. Knapp R. H., Dewald G. W. & Pierre R. V. (1985) Cytogenetic studies in 174 consecutive patients with preleukemic or myelodysplastic syndromes. Muyo Clin. Proc. 60, 507. 6. Maserati E., Casali M., Pasqulai F., Locatelli F., Gianai S.,
Prete L., Zecca M., Invernizzi R. & Bassan R. (1992) Translocation (8;21) in two casesof refractory anemiawith excess of blasts in transformation. Carzcev Genet. Cytogenet. 58, 76. 7. Estey E. H., Trujillo J. M., Cork A., O’Brien S., Beran M.,
Kantarjian H., Keating M., Freireich E. J. & Stass S. (1992) AML-associated cytogenetic abnormalities ((inv)l6, del(16), t(8;21)) in patients with myelodysplastic syndromes.Hemat. Pathol. 6, 43. 8. Sole F., Prieto F., Badia L., Woessner S., Florensa L., Caballin M. R., Coll M. D., BessesC. & Sans-SabrafenJ. (1992) Cytogenetic studies in 112 cases of untreated myelodysplastic syndromes.Cancer Genet. Cytogenet. 64, 12. 9. Kwong Y. L., Liu H. W., Ching L. M., Pollock A. & Chan
L. C. (1993) Translocation (8;21) and multilineage involvement. Am. J. Hematol. 43, 212. 10. Kwong Y. L., Chan V., Wong K. F. & Chan T. K. (1995) The use of the polymerasechain reaction in the detection of AMLl/ETO fusion transcript in t(8;21). Cancer 75,821. 11. Bennett J. M., Catovsky D., Daniel M. T., Flandrin G., Galton D. A. G., Gralnick H. R. & Sultan C. (1985) Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann. Intern. Med. 45, 285. 12. JacobsA. & Clark R. E. (1986) Pathogenesisand clinical variations in the myelodysplastic syndromes. Clin. Haematol. 15, 925. 13. Swirsky D. M., Li Y. S., Matthews J. G., Flemans R. J.,
ReesJ. K. H. & Hayhoe F. G. J. (1984) 8121translocation in acute granulocytic leukaemia: cytological, cytochemical and clinical features.Br. J. Haematol. 56, 199. 14. Trujillo H. M., Cork A., Ahearn M. J., Youness E. L. & McCredie K. B. (1979) Hematologic and cytologic characterizationof S/21 translocation in acute granulocytic leukemia. Blood 53, 695. 15. Groupe Francais de Cytogenetique Hematologique. (1990) Acute myelogenous leukemia with an 8;21 translocation. A report on 148 cases from the Groupe Franqais de CytogCnCtique Hematologique. Cancer Genet. Cytogenet. 44, 169. 16. Mitelman F. (1991) Catalogue of Chromosomal Aberrutions in Cancer, Fourth Ed, p. 575. Wiley Liss, New York. 17. Auger M. J., Ross R. M. & Mackie M. J. (1991) 8;21 translocation with duplication of the der(21) in a patient with myelomonocytic leukemia. Cancer Genet. Cytogenet. 51, 139. 18. Miyoshi H., Shimizu K., Kozu T., Maseki N., Kaneko Y. & Ohki M. (1991) t(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AMLI. Proc. natn. Acad. Sci. USA 88,10431.
Letter to the Editors 19. Erickson P., Gao J., Chang K. S., Look T., Whisenant E., Raimondi S., Lasher R., Trujillo J., Rowley J. & Drabkin H. (1992) Identification of breakpoints in t(8;21) acute myelogenous leukemia and isolation of a fusion transcript, AMLlIETO, with similarity to Drosophila segmentation gene, runt. Blood 80, 1825. 20. Nucifora G., Birn D. J., Erickson P., Gao J., LeBeau M. M., Drabkin H. A. & Rowley J. D. (1993) Detection of DNA rearrangements in the AMLl and ET0 loci and of an AMLliETO fusion mRNA in patients with t&21) acute myelogenous leukemia. Blood 81, 883. 21. Chang K. S., Fan Y. H., Stass S. A., Estey E. H., Wang G., Trujillo J. M., Erickson P. & Drabkin H. (1993) Expression of AMLl-ET0 fusion transcripts and detection of minimal residual disease in t(8;21) positive acute myeloid leukemia. Oncogr/le 8, 893. 22. Nucifora G., Larson R. A. & Rowley J. D. (1993) Persistence of the 8;21 translocation in patients with acute myeloid leukemia type M2 in long-term remission. Blood 82, 712. 23. Kusec R., Lacsika K., Knob1 P., Fried1 J., Greinix H., Kahls P., Linkesch W., Schwarzinger I., Mitterbauer G., Purtscher B., Hass 0. A., Lechner K. & Jaeger U. (1994) AMLl/ETO fusion mRNA can be detected in remission blood samples of all patients with t(8;21) acute myeloid leukemia after chemotherapy or autologous bone marrow transplantation. Leukemia 8, 735. 24. Greaves M. F. (1993) Stem cell origins of leukaemia and curability. Br. J. Cancer 67, 413. 25. Grignani F., Fagioli M., Alcalay M., Longo L., Pandolfi P.P., Donti E., Biondi A., LoCoco F., Grignani F. & Pelicci P.G. (1994) Acute promyelocytic leukemia: from genetics to treatment. Blood 83, 10.
677
26. Pedersen-Bjergaard J., Daugaard G., Hansen S. W., Philip P., Larsen S. 0. & Rorth M. (1991) Increased risk of myelodysplasia and leukaemia after etoposide, cisp’atin and bleomycin for germ cell tumours. Lancet 338, 353. 27. Quesnel B., Kantarjian H., Bjergaard J. P., Brault P., Estey E., Lai J. L., Tilly H., Stoppa A. M., Archimbaud E., Harousseau J. L., Bauters F. & Fenaux P. (1993) Therapyrelated acute myeloid leukemia with t(8;21), inv(l6), and t(8;16): a report on 25 cases and review of the literature. J. clin. Oncol. 11, 2370. 28. Pedersen-Bjergaard J., Philip P., Larsen S.O., Jensen G. & Byrsting K. (1990) Chromosome aberrations and prognostic factors in therapy-related myelodysplasia and acute nonlymphocytic leukemia. Blood 76, 1083. 29. Berger R., Hillion J., Janvier D., Chen Z. & Bussel A. (1993) t(8;21) prior to acute leukemia. Cancer Genet. Cytogenet. 70, 125. 30. Bernheim A., Duverger A., Fouquet F., Bayle C. & Oberlin 0. (1995) FISH diagnosis of t&21) in a myelodysplasia secondary to Hodgkin lymphoma. Leukemia 9, 107.
Y. L. Kwong* and K. F. Wang-F *Division of Hematology, University Department of Medicine, Queen Mary Hospital, Pokfulam Road, Hong Kong; and fDepartment of Pathology, Queen Elizabeth Hospital, Pokfulam Road, Hong Kong