• Features of treatment-related myelodisplastic syndrome and treatment-related acute myeloid leukaemia in children treated for acute lymphoblastic leukaemia: own observations

Features of treatment-related myelodisplastic syndrome and treatment-related acute myeloid leukaemia in children treated for acute lymphoblastic leukaemia: own observations

SOVREMENNAYA PEDIATRIYA.2018.4(92):69-80; doi 10.15574/SP.2018.92.69

Dorosh О. І., Myh A. M., Stepanyuk A. I., Kozlova O. I., Skoropad L. L., Seredych L. P., Tsymbalyuk-Voloshyn I. P.
Municipal Establishment of Lviv Oblast Council «Western Ukrainian Specialized Children's Medical Centre», Ukraine
Danylo Halytsky Lviv National Medical University, Ukraine

The article presents two clinical cases of secondary treatment-related haemoblastosis – treatment-related myelodisplastic syndrome (t-MDS)/treatment-related acute myeloid leukaemia (AML) – t-MDS/t-AML, compared to the data of other world's investigators. Two boys with primary diagnosed acute lymphoblastic leukaemia (ALL) were treated according to the program ALL IC-BFM-2002, depending upon their belonging to intermediate (IRTG) and high-risk treatment groups (HRTG). The secondary MDS associated with monosomy 7 developed in the patient of the intermediate risk group, which was subsequently transformed to secondary AML. After allogenic transplantation of haemopoetic cells of umbilical cord blood, it appeared that the post-transplant complications developed, which caused death of the patient. In another boy from the high-risk group, the secondary AML associated with translocation t(9.11) (p22; q23) was diagnosed. He was provided with allogenic transplantation of haemopoetic cells as well. The patient has been in clinical-haematological remission of ALL for 77 months and clinical-haematological remission of t-AML — 49 months. The t-MDS/t-AML are registered amid supportive chemotherapy of ALL after 20 months in males with chromosome anomalies, predisposed to progress during standard chemotherapy and severe infectious toxic complications associated with cytopenia. The transplantation of haemopoetic cells presents the only treatment regimen for patients with t-MDS/t-AML.
Key words: acute lymphoblastic leukaemia, treatment-related myelodisplastic syndrome, treatment-related acute myeloid leukaemia, secondary neoplasia, children.


1. Bebeshko VH, Klymenko SV. (2002). Biological features and clinical course of secondary leukemia. Onkolohyia. 4(3): 217-224.

2. Domracheva EV, Aseeva EA, Neverova AL et al. (2011). Leukemia and myelodysplastic syndromes that occurred after anticancer therapy: results of 16 years of observation. Klynycheskaia onkohematolohyia. 4(2): 120-133.

3. Alfonso Quintas-Cardama, Naval Daver, Hawk Kim et al. (2014). A prognostic model of therapy related myelodysplastic syndrome for predicting survival and transplantation to acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 14(5): 401—410. https://doi.org/10.1016/j.clml.2014.03.001; PMid:24875590 PMCid:PMC4167474

4. Anderson JE, Gooley TA, Schoch G et al. (1997). Stem cell transplantation for secondary acute myeloid leukemia: evaluation of transplantation as initial therapy or following induction chemotherapy. Blood. 89: 2578—2585. PMid:9116305

5. Aung L, Khyne T, Yeoh AE et al. (2009). A report from the Singapore Childhood Cancer Survivor Study (SG-CCSS): a multi-institutional collaborative study on long$term survivors of childhood cancer, initial analysis reporting for the SG-CCSS. Ann Acad Med Singapore. 38(8): 684—689. PMid:19736571

6. Barry EV, Vrooman LM, Dahlberg SE et al. (2008). Absence of secondary malignant neoplasms in children with high-risk acute lymphoblastic leukemia treated with dexrazoxane. J Clin Oncol. 26(7): 1106—1111. https://doi.org/10.1200/JCO.2007.12.2481; PMid:18309945

7. Bhatia S. (2013). Therapy-related myelodysplasia and acute myeloid leukemia. Semin Oncol. 40(6): 666—675. https://doi.org/10.1053/j.seminoncol.2013.09.013; PMid:24331189 PMCid:PMC3867743

8. Bloomfield CD, Archer KJ, Mrozek K et al. (2002). 11q23 balanced chromosome aberrations in treatment-related myelodysplastic syndromes and acute leukemia: report from an international workshop. Genes Chromosomes Cancer. 33(4): 362—378. https://doi.org/10.1002/gcc.10046; PMid:11921271

9. Boice JDJr, Fraumeni JFJr, Tucker MA et al. (1984). Cancer risk following treatment of childhood cancer. In JDJr Boice, FJJr Traumeni (Eds). Radiation carcinogenesis: epidemiology and biological significance. New York: Raven Press: 211—224.

10. Brunning RD, Matutes E, Flandrin G et al. (2001). Acute myeloid leukaemias and myelodysplastic syndromes, therapy related. In ES Jaffe, NL Harris, H Stein et al. (Eds.). World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press: 89—91.

11. Chandra P, Luthra R, Zuo Z et al. (2010). Acute myeloid leukemia with t(9;11) (p21$22;q23): common properties of dysregulated ras pathway signaling and genomic progression characterize de novo and therapy$related cases. Am J Clin Pathol. 133(5): 686—693. https://doi.org/10.1309/AJCPGII1TT4NYOGI; PMid:20395514

12. Cornelissen JJ, Breems D, van Putten WL et al. (2012). Comparative analysis of the value of allogeneic hematopoietic stem-cell transplantation in acute myeloid leukemia with monosomal karyotype versus other cytogenetic risk categories. J Clin Oncol. 30: 2140—2146. https://doi.org/10.1200/JCO.2011.39.6499; PMid:22564995

13. Dalton VMK, Gelber RD, Li F et al. (1998). Second malignancies in patients treated for childhood acute lymphoblastic leukemia. J Clin Oncol. 16: 2848—2853. https://doi.org/10.1200/JCO.1998.16.8.2848; PMid:9704738

14. De Lima M, Parmar S, Chen J et al. (2012). Low dose azacitidine (AZA) reduces the incidence of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Blood. 120: 742.

15. Essig S, Li Q, Chen Y et al. (2014). Risk of late effects of treatment in children newly diagnosed with standard$risk acute lymphoblastic leukaemia: a report from the Childhood Cancer Survivor Study cohort. Lancet Oncol. 15(8): 841—851. https://doi.org/10.1016/S1470-2045(14)70265-7

16. Estey E, Dohner H (2006). Acute myeloid leukaemia. Lancet. 368(9550): 1894—1907. https://doi.org/10.1016/S0140-6736(06)69780-8

17. Felice MS, Rossi JG, Alonso CN et al. (2017). Second neoplasms in children following a treatment for acute leukemia and/or lymphoma: 29 years of experience in a single Institution in Argentina. J Pediatr Hematol Oncol. 39(8): 406—412. https://doi.org/10.1097/MPH.0000000000000971; PMid:28945661

18. Fisher KE, Hsu AP, Williams CL et al. (2017). Somatic mutations in children with GATA2-associated myelodysplastic syndrome who lack other features of GATA2 deficiency. Blood Adv. 28; 1(7): 443—448.

19. Gaynon PS, Angiolillo AL, Carroll WL et al.; Children's Oncology Group (2010). Long$term results of the children's cancer group studies for childhood acute lymphoblastic leukemia 1983—2002: a Children's Oncology Group Report. Leukemia. 24(2):285—297. https://doi.org/10.1038/leu.2009.262; PMid:20016531 PMCid:PMC2906139

20. Godley LA, Larson RA. (2002). The syndrome of therapy$related myelodysplasia and myeloid leukemia. In JM Bennett (Editor). The myelodysplastic syndromes: pathobiology and clinical management. New York: Marcel Dekker, Inc:139—176.

21. Godley LA, Larson RA. (2008). Therapy$related myeloid leukemia. Semin Oncol. 35(4):418—429. https://doi.org/10.1053/j.seminoncol.2008.04.012; PMid:18692692 PMCid:PMC2600445

22. Greene MH, Harris EL, Gershenson DM et al. (1986). Melphalan may be a more potent leukemogen than cyclophosphamide. Ann Intern Med. 105:360—367. https://doi.org/10.7326/0003-4819-105-3-360; PMid:3740675

23. Haddy TB, Mosher RB, Reaman GH. (2009). Late effects in long-term survivors after treatment for childhood acute leukemia. Clin Pediatr (Phila). 48(6):601—608. https://doi.org/10.1177/0009922809332680; PMid:19264722

24. Heim S. (1992). Cytogenetic findings in primary and secondary MDS. Leuk Res.16(1):43—6. https://doi.org/10.1016/0145-2126(92)90098-R

25. Ishida Y, Maeda M, Urayama KY et al.; QOL committee of Tokyo Children's Cancer Study Group (TCCSG). (2014). Secondary cancers among children with acute lymphoblastic leukaemia treated by the Tokyo Children's Cancer Study Group protocols: a retrospective cohort study. Br J Haematol. 164(1):101—112. https://doi.org/10.1111/bjh.12602; PMid:24116892

26. Jaime-Perez JC, Lopez-Razo ON, Garcia-Arellano G et al. (2016). Results of treating childhood acute lymphoblastic leukemia in a low-middle income country: 10 year experience in Northeast Mexico. Arch Med Res.47(8):668—676. https://doi.org/10.1016/j.arcmed.2017.01.004; PMid:28476194

27. Koh KN, Yoo KH, Im HJ et al. (2016). Characteristics and outcomes of second malignant neoplasms after childhood cancer treatment: multi-center retrospective survey. J Korean Med Sci.31(8):1254—1261. https://doi.org/10.3346/jkms.2016.31.8.1254; PMid:27478336 PMCid:PMC4951555

28. Kollmannsberger C, Hartmann JT, Kanz L, Bokemeyer C. (1998). Risk of secondary myeloid leukemia and myelodysplastic syndrome following standard-dose chemotherapy or high-dose chemotherapy with stem cell support in patients with potentially curable malignancies. J Cancer Res Clin Oncol. 124(3—4):207—14. https://doi.org/10.1007/s004320050156; PMid:9619748

29. Krishnan A, Bhatia S, Slovak ML et al. (2000). Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation for lymphoma: an assessment of risk factors. Blood. Mar 1. 95(5):1588—93.

30. Levinsen M, Rotevatn EO, Rosthoj S et al.; Nordic Society of Paediatric Haematology, Oncology. (2014). Pharmacogenetically based dosing of thiopurines in childhood acute lymphoblastic leukemia: influence on cure rates and risk of second cancer. Pediatr Blood Cancer. 61(5):797—802. https://doi.org/10.1002/pbc.24921; PMid:24395436

31. Lo Nigro L, Bottino D, Panarello C et al. (2003). Prognostic impact of t(9;11) in childhood acute myeloid leukemia (AML). Leukemia. 17:636—656. https://doi.org/10.1038/sj.leu.2402846; PMid:12646956

32. Loning L, Zimmermann M, Reiter A et al. (2000). Secondary neoplasms subsequent to Berlin-Frankfurt-Munster therapy of acute lymphoblastic leukemia in childhood: significantly lower risk without cranial therapy. Blood. 95: 2770—2775. PMid:10779419

33. Maniar TN, Braunstein I, Keefe S et al. (2007). Childhood ALL and second neoplasms. Cancer Biol Ther. 6(10):1525—1531. https://doi.org/10.4161/cbt.6.10.4928; PMid:17952026

34. Maung SW, Burke C, Hayde J et al. (2017). A review of therapy-related myelodysplastic syndromes and acute myeloid leukaemia (t-MDS/AML) in Irish patients: a single centre experience. Hematology. 22(6):341—346. https://doi.org/10.1080/10245332.2017.1286539; PMid:28196450

35. Mauritzson N, Albin M, Rylander L et al. (2002). Pooled analysis of clinical and cytogenetic features in treatment$related and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976—1993 and on 5098 unselected cases reported in the literature 1974—2001. Leukemia. 16(12):2366—2378. https://doi.org/10.1038/sj.leu.2402713; PMid:12454741

36. Mitchell C, Richards S, Harrison CJ, Eden T. (2010). Long-term follow-up of the United Kingdom medical research council protocols for childhood acute lymphoblastic leukaemia, 1980—2001. Leukemia. 24(2):406—418. https://doi.org/10.1038/leu.2009.256; PMid:20010621 PMCid:PMC2820452

37. Mody R, Li S, Dover DC et al. (2008). Twenty-five-year follow$up among survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. Blood. 111(12): 5515—5523. https://doi.org/10.1182/blood-2007-10-117150; PMid:18334672 PMCid:PMC2424150

38. Neglia JP, Meadows AT, Robison LL et al. (1991). Second neoplasms after acute lymphoblastic leukemia in childhood. N Engl J Med. 325:1330—1336. https://doi.org/10.1056/NEJM199111073251902; PMid:1922234

39. Ng AK, Kenney LB, Gilbert ES, Travis LB. (2010). Secondary malignancies across the age spectrum. Semin Radiat Oncol. 20(1): 67—78. https://doi.org/10.1016/j.semradonc.2009.09.002; PMid:19959033 PMCid:PMC3857758

40. Nielsen SN, Eriksson F, Rosthoej S et al. (2017). Children with low-risk acute lymphoblastic leukemia are at highest risk of second cancers. Pediatr Blood Cancer. 64(10). https://doi.org/10.1002/pbc.26518

41. Nygaard R, Garwicz S, Haldorsen T et al. (1991). Second malignant neoplasms in patients treated for childhood leukemia. Acta Paediatr Scand. 80:1220—1228. https://doi.org/10.1111/j.1651-2227.1991.tb11812.x; PMid:1785295

42. Olney HJ, Mitelman F, Johansson B et al. (2002). Unique balanced chromosome abnormalities in treatment-related myelodysplastic syndromes and acute myeloid leukemia: report from an international workshop. Genes Chromosomes Cancer. 33: 413—423. https://doi.org/10.1002/gcc.10045; PMid:11921275

43. Ornstein MC, Mukherjee S, Mohan S et al. (2014). Predictive factors for latency period and a prognostic model for survival in patients with therapy-related AML. Am. J. Hematol. 89(2): 168—173. https://doi.org/10.1002/ajh.23605; PMid:24123154

44. Paganin M, Buldini B, Germano G et al. (2016). A case of T-cell acute lymphoblastic leukemia relapsed as myeloid acute leukemia. Pediatr Blood Cancer.63(9):1660—1663. https://doi.org/10.1002/pbc.26054; PMid:27149388

45. Pedersen-Bjergaard J, Andersen MK, Christiansen DH. (2000). Therapy-related acute myeloid leukemia and myelodysplasia after high-dose chemotherapy and autologous stem cell transplantation. Blood. 95(11):3273—3279. PMid:10828005

46. Perkins SM, Dewees T, Shinohara ET, Reddy MM, Frangoul H. (2013). Risk of subsequent malignancies in survivors of childhood leukemia. J Cancer Surviv. 7(4):544—550. https://doi.org/10.1007/s11764-013-0292-8; PMid:23749687

47. Platzbecker U, Wermke M, Radke J et al. (2012). Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia.26:381—389. https://doi.org/10.1038/leu.2011.234; PMid:21886171 PMCid:PMC3306138

48. Pratt CB, George SL, Hannock ML et al. (1988). Second malignant neoplasms in survivors of childhood acute lymphocytic leukemia [abstract]. Pediatr Res. 23:345.

49. Pui CH, Behm FG, Raimondi SC et al. (1989). Secondary acute myeloid leukemia in children treated for acute lymphoid leukemia. N Engl J Med. 321(3):136—142. https://doi.org/10.1056/NEJM198907203210302; PMid:2787477

50. Pui CH, Campana D, Pei D et al. (2009). Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 360(26): 2730—2741. https://doi.org/10.1056/NEJMoa0900386; PMid:19553647 PMCid:PMC2754320

51. Pui CH, Pei D, Campana D et al. (2014). A revised definition for cure of childhood acute lymphoblastic leukemia. Leukemia. 28(12):2336—2343. https://doi.org/10.1038/leu.2014.142; PMid:24781017 PMCid:PMC4214904

52. Renard M, Suciu S, Bertrand Y et al.; EORTC Children Leukaemia Group (CLG). (2011). Second neoplasm in children treated in EORTC 58881 trial for acute lymphoblastic malignancies: low incidence of CNS tumours. Pediatr Blood Cancer. 57(1):119—125. https://doi.org/10.1002/pbc.23083; PMid:21412967

53. Rihani R, Bazzeh F, Faqih N, Sultan I. (2010). Secondary hematopoietic malignancies in survivors of childhood cancer: an analysis of 111 cases from the Surveillance, Epidemiology, and End Result-9 registry. Cancer. 116(18): 4385—4394. https://doi.org/10.1002/cncr.25313; PMid:20549819

54. Rowley JD, Olney HJ. (2002). International workshop on the relationship of prior therapy to balanced chromosome aberrations in therapy-related myelodysplastic syndromes and acute leukemia: overview report. Genes Chromosomes Cancer. 33:331—345. https://doi.org/10.1002/gcc.10040; PMid:11921269

55. Rubnitz JE, Raimondi SC, Tong X et al. (2002). Favorable impact of the t(9;11) in childhood acute myeloid leukemia. J Clin Oncol. 20:2302—2309. https://doi.org/10.1200/JCO.2002.08.400; https://doi.org/10.1200/JCO.2002.08.023

56. Schmiegelow K, Levinsen MF, Attarbaschi A et al. (2013). Second malignant neoplasms after treatment of childhood acute lymphoblastic leukemia. J Clin Oncol. 31(19):2469—2476. https://doi.org/10.1200/JCO.2012.47.0500; PMid:23690411 PMCid:PMC3807139

57. Schroeder T, Czibere A, Kroger N et al. (2011). Phase II study of azacitidine (Vidaza®, Aza) and donor lymphocyte infusions (DLI) as first salvage therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) relapsing after allogeneic hematopoietic stem cell transplantation (allo-SCT): final results from the AZARELA trial (NCT-00795548). Blood. 118: abs. 656.17.

58. Singh ZN, Huo D, Anastasi J et al. (2007). Therapy-related myelodysplastic syndrome: morphologic subclassification may not be clinically relevant. Am J Clin Pathol. 127(2): 197—205. https://doi.org/10.1309/NQ3PMV4U8YV39JWJ; PMid:17210514

59. Smita Bhatia, Harland N Sather, Olga B Pabustan et al. (2002). Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983. Blood. 99: 4257—4264. https://doi.org/10.1182/blood.V99.12.4257; PMid:12036851

60. Smith SM, Le Beau MM, Huo D et al. (2003). Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood. 102: 43—52. https://doi.org/10.1182/blood-2002-11-3343; PMid:12623843

61. Sun WF, Cheng FW, Lee V et al. (2011). Second malignant neoplasms in childhood cancer survivors in a tertiary paediatric oncology centre in Hong Kong, China. Chin Med J (Engl). 124(22): 3686—3692.

62. Tai EW, Ward KC, Bonaventure A, Siegel DA, Coleman MP. (2017). Survival among children diagnosed with acute lymphoblastic leukemia in the United States, by race and age, 2001 to 2009: Findings from the CONCORD-2 study. Cancer. 123(24): 5178—5189. https://doi.org/10.1002/cncr.30899; PMid:29205314 PMCid:PMC6075705

63. Takeyama K, Seto M, Uike N et al. (2000). Therapy-related leukemia and myelodysplastic syndrome: a large-scale Japanese study of clinical and cytogenetic features as well as prognostic factors. Int J Hematol. 71: 144—152. PMid:10745624

64. Tebbi CK, London WB, Friedman D et al. (2007). Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J Clin Oncol. 25(5): 493—500. https://doi.org/10.1200/JCO.2005.02.3879; PMid:17290056

65. Teng CJ, Huon LK, Hu YW et al. (2016). Secondary solid organ neoplasm in patients with acute lymphoblastic leukemia: a Nationwide Population-Based Study in Taiwan. PLoS One. 11(4): e0152909. https://doi.org/10.1371/journal.pone.0152909; PMid:27035574 PMCid:PMC4817987

66. Tragiannidis A, Gombakis N, Papageorgiou M et al. (2016). Treatment-related myelodysplastic syndrome (t-MDS)/acute myeloid leukemia (AML) in childrenwith cancer: a single-center experience. Int J Immunopathol Pharmacol. 29(4): 729—730. https://doi.org/10.1177/0394632016670667; PMid:27647464 PMCid:PMC5806816

67. Travis LB, Rabkin CS, Brown LM et al. (2006). Cancer survivorship — genetic susceptibility and second primary cancers: research strategies and recommendations. J Natl Cancer Inst. 98(1): 15—25. https://doi.org/10.1093/jnci/djj001; PMid:16391368

68. Turcotte LM, Liu Q, Yasui Y et al. (2017). Temporal trends in treatment and subsequent neoplasm risk among 5-year survivors of childhood cancer, 1970—2015. JAMA. 317(8): 814—824. https://doi.org/10.1001/jama.2017.0693; PMid:28245323 PMCid:PMC5473951

69. Valentina Nardi, Karen M Winkfield, Chi Y Ok et al. (2012). Acute myeloid leukemia and myelodysplastic syndromes after radiation therapy are similar to de novo disease and differ from other therapy-related myeloid neoplasms. J Clin Oncol. 30(19): 2340—2347. https://doi.org/10.1200/JCO.2011.38.7340; PMid:22585703 PMCid:PMC4979234

70. Van Gelder M, de Wreede LC, Schetelig J et al. (2013). Monosomal karyotype predicts poor survival after allogeneic stem cell transplantation in chromosome 7 abnormal myelodysplastic syndrome and secondary acute myeloid leukemia. Leukemia. 27: 879—888. https://doi.org/10.1038/leu.2012.297; PMid:23164802

71. Vardiman JW, Brunning RD, Larson RA et al. (2008). Therapy-related myeloid neoplasms. In: Swerdlow SH, Campo E, Harris NL et al. (Eds.). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press: 127—129.

72. Vrooman LM, Neuberg DS, Stevenson KE et al. (2011). The low incidence of secondary acute myelogenous leukaemia in children and adolescents treated with dexrazoxane for acute lymphoblastic leukaemia: a report from the Dana-Farber Cancer Institute ALL Consortium. Eur J Cancer. 47(9): 1373—1379. https://doi.org/10.1016/j.ejca.2011.03.022; PMid:21514146 PMCid:PMC3736806

73. Westermeier T, Kaatsch P, Schoetzau A, Michaelis J. (1998). Multiple primary neoplasms in childhood: the data from the German Children's Cancer Registry. Eur J Cancer. 34: 687. https://doi.org/10.1016/S0959-8049(97)00326-2

74. Wierzbowska A, Wawrzyniak E, Szmigielska-Kaplon A et al. (2013). Wtorna ostra bialaczka szpikowa u chorej po skutecznym leczeniu ostrej bialaczki promielocytowej. Hematologia. 4(4): 358—362.

75. Zahid MF, Parnes A, Savani BN, Litzow MR, Hashmi SK. (2016). Therapy-related myeloid neoplasms — what have we learned so far? World J Stem Cells. 8(8): 231—242. https://doi.org/10.4252/wjsc.v8.i8.231; PMid:27621757 PMCid:PMC4999650

76. Zhang L, Wang SA. (2014). A focused review of hematopoietic neoplasms occurring in the therapy-related setting. Zhang L, Wang SA.Int J Clin Exp Pathol. 7(7): 3512—3523. PMid:25120730 PMCid:PMC4128965

77. Zhao N, Stoffel A, Wang PW et al. (1997). Molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases to 1—1.5 Mb and preparation of a PAC-based physical map. Proc Natl Acad Sci USA. 94: 6948—6953. https://doi.org/10.1073/pnas.94.13.6948; PMid:9192672