Infant acute leukemia with lineage switch at relapse expressing a novel t(4;11)(q21;q23) MLL-AF4 fusion transcript

Open access


Background. A high occurrence of translocation t(4;11)(q21;q23) was reported in infant acute lymphoblastic leukemia (ALL) leading to the fusion of the mixed lineage leukemia (MLL) gene on chromosome 11 and the AF4 gene on chromosome 4. More than 50 distinct MLL-AF4 types of fusion have been previously identified, none of those reported matching the peculiarities found in an infant ALL case to be reported below. Materials and methods. Molecular tests were performed for the detection of TEL-AML1, BCR-ABL(p190), E2A-PBX1, and MLL-AF4 in the peripheral blood sample of a 21 days new-born boy suspected of ALL. An unexpected MLL-AF4 fragment was identified, further purified, and later analyzed by sequencing. Flow cytometry analyses were carried out at diagnosis and relapse on a FACSCanto-II cytometer (Becton-Dickinson). Results. The patient was found to be positive for the MLL-AF4 transcript, with an uncommonly long-sized product and a previously undescribed sequence (in-frame fusion between exon 12 of MLL and exon 4 of the AF4 gene). The immunophenotypic analyses also showed a particular development: while at diagnosis a dominant malignant clone displaying a B lymphoid precursor phenotype was described, at relapse a malignant monocytoid population predominantly expanded. The presence of MLL-AF4 e12-e4 transcript was still manifest at relapse, without other transcript characteristic for myeloid lineage. Conclusions. To our knowledge, this is the first report of a MLL-AF4 rearrangement revealing this complex transcript with new breakpoints in MLL. Its early detection may predict an immunophenotypic switch and may assist the clinicians in designing optimized therapies.

1. De Braekeleer E, Douet-Guilbert N, Le Bris MJ, Basinko A, Morel F, De Braekeleer M. Gene expression profiling of adult t(4;11)(q21;q23)-associated acute lymphoblastic leukemia reveals a different signature from pediatric cases. Anticancer Res. 2012 Sep;32(9):3893-9

2. De Braekeleer M, Morel F, Le Bris MJ, Herry A, Douet-Guilbert N. The MLL gene and translocations involving chromosomal band 11q23 in acute leukemia. Anticancer Res. 2005 May-Jun;25(3B):1931-44

3. Drexler HG, Quentmeier H, MacLeod RA. Malignant hematopoietic cell lines: in vitro models for the study of MLL gene alterations. Leukemia. 2004 Feb;18(2):227-32

4. Super HG, Strissel PL, Sobulo OM, Burian D, Reshmi SC, Roe B, Zeleznik-Le NJ, et al. Identification of complex genomic breakpoint junctions in thet(9;11) MLL-AF9 fusion gene in acute leukemia. Genes Chromosomes Cancer. 1997 Oct;20(2):185-95

5. Pui CH, Evans WE. Acute lymphoblastic leukemia. N Engl J Med. 1998 Aug 27;339(9):605-15

6. Pui CH, Kane JR, Crist WM. Biology and treatment of infant leukemias. Leukemia. 1995 May;9(5):762-9

7. Ludwig W D, Rieder H, Bartram C R, Heinze B, Schwartz S, Gassmann W, et al. Immunophenotypic and genotypic features, clinical characteristics and treatment outcome of adult pro-B acute lymphoblastic leukemia: results of the German multicenter trials GMALL03/87 and 04/89. Blood 1998; 92:1898-1909

8. van Dongen JJ, Macintyre EA, Gabert JA, Delabesse E, Rossi V, Saglio G, et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia. 1999 Dec;13(12):1901-28

9. Felix CA, Hosler MR, Slater DJ, Parker RI, Masterson M, Whitlock JA, et al. MLL genomic breakpoint distribu- tion within the breakpoint cluster region in de novo leukemia in children. J Pediatr Hematol Oncol. 1998 Jul- Aug;20(4):299-308

10. Reichel M, Gillert E, Angermüller S, Hensel JP, Heidel F, Lode M, et al. Biased distribution of chromosomal breakpoints involving the MLL gene in infants versus children and adults with t(4;11) ALL. Oncogene. 2001 May 24;20(23):2900-7

11. Muñoz L, Nomdedéu JF, Villamor N, Guardia R, Colomer D, Ribera JM, et al. Acute myeloid leukemia with MLL rearrangements: clinicobiological features, prognostic impact and value of flow cytometry in the detection of residual leukemic cells. Leukemia. 2003 Jan;17(1):76-82

12. Marcucci G, Strout MP, Bloomfield CD, Caligiuri MA. Detection of unique ALL1 (MLL) fusion transcripts in normal human bone marrow and blood: distinct origin of normal versus leukemic ALL1 fusion transcripts. Cancer Res. 1998 Feb 15;58(4):790-3

13. Jansen MW, Corral L, van der Velden VH, Panzer- Grümayer R, Schrappe M, Schrauder A, et al. Immunobiological diversity in infant acute lymphoblastic leukemia is related to the occurrence and type of MLL gene rearrangement. Leukemia. 2007 Apr;21(4):633-41

14. Hagemeijer A, van Dongen JJ, Slater RM, van't Veer MB, Behrendt H, Hählen K, et al. Characterization of the blast cells in acute leukemia with translocation (4;11): report of eight additional cases and of one case with a variant translocation. Leukemia. 1987 Jan;1(1):24-3

15. Gleissner B, Goekbuget N, Rieder H, Arnold R, Schwartz S, Diedrich H, et al. CD10- pre-B acute lymphoblastic leukemia (ALL) is a distinct high-risk subgroup of adult ALL associated with a high frequency of MLL aberrations: results of the German Multicenter Trials for Adult ALL (GMALL). Blood. 2005 Dec 15;106(13):4054-6

16. Abdelhaleem M. Frequent but nonrandom expression of myeloid markers on de novo childhood acute lymphoblastic leukemia. Exp Mol Pathol. 2007 Aug;83(1):138-41

17. Supriyadi E, Veerman AJ, Sutaryo, Purwanto I, Vd Ven PM, Cloos J. Myeloid Antigen Expression in Childhood Acute Lymphoblastic Leukemia and Its Relevance for Clinical Outcome in Indonesian ALL-2006 Protocol. J Oncol. 2012;2012:135186

18. Griesinger F, Elfers H, Ludwig WD, Falk M, Rieder H, Harbott J, et al. Detection of HRX-FEL fusion transcripts in pre-pre-B-ALL with and without cytogenetic demonstration of t(4;11). Leukemia. 1994 Apr;8(4):542-8

19. Behm FG, Smith FO, Raimondi SC, Pui CH, Bernstein ID. Human homologue of the rat chondroitin sulfate proteoglycan, NG2, detected by monoclonal antibody 7.1, identifies childhood acute lymphoblastic leukemias with t(4;11)(q21;q23) or t(11;19)(q23;p13) and MLL gene rearrangements. Blood. 1996 Feb 1;87(3):1134-9

20. Borowitz MJ, Béné M-C, Harris NL, Porwit A, Matutes E. Acute leukaemias of ambiguous lineage. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: WHO Press; 2008. p. 150-5

21. Béné MC, Porwit A. Acute leukemias of ambiguous lineage. Semin Diagn Pathol. 2012 Feb;29(1):12-8

22. Béné MC, Castoldi G, Knapp W, Ludwig WD, Matutes E, Orfao A, et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia 1995;9:1783-6

23. Catovsky D, Matutes E, Buccheri V, Shetty V, Hanslip J, Yoshida N, et al. A classification of acute leukaemia for the 1990s. Ann Hematol 1991;62:16-21

24. Chen CS, Sorensen PH, Domer PH, Reaman GH, Korsmeyer SJ, Heerema NA, et al. Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome. Blood. 1993 May 1;81(9):2386-93

25. Rubnitz JE, Link MP, Shuster JJ, Carroll AJ, Hakami N, Frankel LS, et al. Frequency and prognostic significance of HRX rearrangements in infant acute lymphoblastic leukemia: a Pediatric Oncology Group study. Blood. 1994 Jul 15;84(2):570-3

26. van der Linden MH, Creemers S, Pieters R. Diagnosis and management of neonatal leukaemia. Semin Fetal Neonatal Med. 2012 Aug;17(4):192-5

27. Zhang Y, Wu D, Sun A, Qiu H, He G, Jin Z, et al. Clinical characteristics, biological profile, and outcome of biphenotypic acute leukemia: a case series. Acta Haematol. 2011;125(4):210-8

28. Hughes TP, Morgan GJ, Martiat P, Goldman JM. Detection of residual leukemia after bone marrow transplant for chronic myeloid leukemia: role of polymerase chain reaction in predicting relapse. Blood. 1991;77(4):874-8

29. Gabert J, Beillard E, van der Velden VH, Bi W, Grimwade D, Pallisgaard N, et al. Standardization and quality control studies of 'real-time' quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia - a Europe Against Cancer program. Leukemia. 2003 Dec;17(12):2318-57

30. Gerr H, Zimmermann M, Schrappe M, Dworzak M, Ludwig WD, Bradtke J, et al. Acute leukaemias of ambiguous lineage in children: characterization, prognosis and therapy recommendations. Br J Haematol. 2010 Apr;149(1):84-92

31. Sakaki H, Kanegane H, Nomura K, Goi K, Sugita K, Miura M, Ishii E, Miyawaki T. Early lineage switch in an infant acute lymphoblastic leukemia. Int J Hematol 2009; 90: 653-5

32. Stasik C, Ganguly S, Cunningham MT, Hagemeister S, Persons DL. Infant acute lymphoblastic leukemia with t(11;16)(q23;p13.3) and lineage switch into acute monoblastic leukemia. Cancer Genet Cytogenet 2006; 168: 146-9

33. Jiang JG, Roman E, Nandula SV, Murty VV, Bhagat G, Alobeid B. Congenital MLL-positive B-cell acute lymphoblastic leukemia (B-ALL) switched lineage at relapse to acute myelocytic leukemia (AML) with persistent t(4;11) and t(1;6) translocations and JH gene rearrangement. Leuk Lymphoma 2005; 46: 1223-7

34. Park M, Koh KN, Kim BE, Im HJ, Jang S, Park CJ, Chi HS, Seo JJ. Lineage switch at relapse of childhood acute leukemia: a report of four cases. J Korean Med Sci. 2011 Jun;26(6):829-31

35. Lou Z, Zhang CC, Tirado CA, Slone T, Zheng J, Zaremba CM, Oliver D, Chen W. Infantile mixed phenotype acute leukemia (bilineal and biphenotypic) with t(10;11) (p12;q23);MLL-MLLT10. Leuk Res. 2010 Aug;34(8):1107-9

Revista Romana de Medicina de Laborator

Romanian Journal of Laboratory Medicine

Journal Information

IMPACT FACTOR 2018: 0,800
5-year IMPACT FACTOR: 0,655

CiteScore 2017: 0.31

SCImago Journal Rank (SJR) 2018: 0.194
Source Normalized Impact per Paper (SNIP) 2018: 0.306

Cited By


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 243 185 32
PDF Downloads 116 104 16