Abstract
Acute lymphoblastic leukemia (ALL) in infants under 1 year is strongly associated with translocations involving 11q23 (MLL gene), CD10-negative B-lineage (proB) immunophenotype, and poor outcome. The present study analyses the relationship between age, MLL rearrangements, proB-lineage, and in vitro drug resistance determined using the MTT assay. Compared to 425 children aged over 1 year with common/preB (c/preB) ALL, the 44 infants were highly resistant to steroids (for prednisolone (PRED) more than 580-fold, P=0.001) and L-asparaginase (L-ASP) (12-fold, P=0.001), but more sensitive to cytarabine (AraC) (1.9-fold, P=0.001) and 2-chlorodeoxyadenosine (2-CdA) (1.7-fold, P<0.001). No differences were found for vincristine, anthracyclines, thiopurines, epipodophyllotoxines, or 4-hydroperoxy (HOO)-ifosfamide. ProB ALL of all ages had a profile similar to infant ALL when compared with the group of c/preB ALL: relatively more resistant to L-ASP and PRED (and in addition thiopurines), and more sensitive to AraC and 2-CdA. Age was not related to cellular drug resistance within the proB ALL group (<1 year, n=32, vs ⩾1 year, n=19), nor within the MLL-rearranged ALL (<1 year, n=34, vs ⩾1 year, n=8). The translocation t(4;11)(q21;q23)-positive ALL cases were more resistant to PRED (>7.4-fold, P=0.033) and 4-HOO-ifosfamide (4.4-fold, P=0.006) than those with other 11q23 abnormalities. The expression of P-glycoprotein, multidrug-resistance protein, and lung-resistance protein (LRP) was not higher in infants compared to older c/preB ALL patients, but LRP was higher in proB ALL and MLL-rearranged ALL of all ages. In conclusion, infants with ALL appear to have a distinct in vitro resistance profile with the proB immunophenotype being of importance. The role of MLL cannot be excluded, with the t(4;11) being of special significance, while age appears to play a smaller role.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Biondi A, Cimino G, Pieters R, Pui CH . Biological and therapeutic aspects of infant leukemia. Blood 2000; 96: 24–33.
Pui CH, Gaynon PS, Boyett JM, Chessells JM, Baruchel A, Kamps W et al. Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region. Lancet 2002; 359: 1909–1915.
Rubnitz JE, Behm FG, Downing JR . 11q23 rearrangements in acute leukemia. Leukemia 1996; 10: 74–82.
Heerema NA, Sather HN, Ge J, Arthur DC, Hilden JM, Trigg ME et al. Cytogenetic studies of infant acute lymphoblastic leukemia: poor prognosis of infants with t(4;11) – a report of the Children's Cancer Group. Leukemia 1999; 13: 679–686.
Reaman GH, Sposto R, Sensel MG, Lange BJ, Feusner JH, Heerema NA et al. Treatment outcome and prognostic factors for infants with acute lymphoblastic leukemia treated on two consecutive trials of the Children's Cancer Group. J Clin Oncol 1999; 17: 445–455.
Dordelmann M, Reiter A, Borkhardt A, Ludwig WD, Gotz N, Viehmann S et al. Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia. Blood 1999; 94: 1209–1217.
Pieters R, Den Boer ML, Durian M, Janka G, Schmiegelow K, Kaspers GJL et al. Relation between age, immunophenotype and in vitro drug resistance in 395 children with acute lymphoblastic leukemia – implications for treatment of infants. Leukemia 1998; 12: 1344–1348.
Scheper RJ, Broxterman HJ, Scheffer GL, Kaaijk P, Dalton WS, Van Heijningen T et al. Overexpression of a M(r) 110,000 vesicular protein in non-P-glycoprotein-mediated multidrug resistance. Cancer Res 1993; 53: 1475–1479.
Scheffer GL, Wijngaard PL, Flens MJ, Izquierdo MA, Slovak ML, Pinedo HM et al. The drug resistance-related protein LRP is the human major vault protein. Nat Med 1995; 1: 578–582.
Den Boer ML, Pieters R, Veerman AJP . Mechanisms of cellular anthracycline resistance in childhood acute leukemia. Leukemia 1998; 12: 1657–1670.
Van Den Heuvel-Eibrink MM, Sonneveld P, Pieters R . The prognostic significance of membrane transport-associated multidrug resistance (MDR) proteins in leukemia. Int J Clin Pharmacol Ther 2000; 38: 94–110.
Den Boer ML, Pieters R, Kazemier KM, Rottier MM, Zwaan CM, Kaspers GJL et al. Relationship between major vault protein/lung resistance protein, multidrug resistance-associated protein, P-glycoprotein expression, and drug resistance in childhood leukemia. Blood 1998; 91: 2092–2098.
Pieters R, Loonen AH, Huismans DR, Broekema GJ, Dirven MW, Heyenbrok MW et al. In vitro drug sensitivity of cells from children with leukemia using the MTT assay with improved culture conditions. Blood 1990; 76: 2327–2336.
Kaspers GJL, Veerman AJP, Pieters R, Broekema GJ, Huismans DR, Kazemier KM et al. Mononuclear cells contaminating acute lymphoblastic leukaemic samples tested for cellular drug resistance using the methyl-thiazol-tetrazolium assay. Br J Cancer 1994; 70: 1047–1052.
Kaspers GJL, Pieters R, Van Zantwijk CH, De Laat PA, De Waal FC, Van Wering ER et al. In vitro drug sensitivity of normal peripheral blood lymphocytes and childhood leukaemic cells from bone marrow and peripheral blood. Br J Cancer 1991; 64: 469–474.
Pieters R, Huismans DR, Leyva A, Veerman AJP . Adaptation of the rapid automated tetrazolium dye based (MTT) assay for chemosensitivity testing in childhood leukemia. Cancer Lett 1988; 41: 323–332.
Hernandez JM, Mecucci C, Beverloo HB, Selleri L, Wlodarska I, Stul M et al. Htrx. Translocation (11–15)(Q23–Q14) in three patients with acute non-lymphoblastic leukemia (ANLL) – clinical, cytogenetic and molecular studies. Leukemia 1995; 9: 1162–1166.
Harbott J, Viehmann S, Borkhardt A, Henze G, Lampert F . Incidence of TEL/AML1 fusion gene analyzed consecutively in children with acute lymphoblastic leukemia in relapse. Blood 1997; 90: 4933–4937.
Repp R, Borkhardt A, Haupt E, Kreuder J, Brettreich S, Hammermann J et al. Detection of four different 11q23 chromosomal abnormalities by multiplex-PCR and fluorescence-based automatic DNA-fragment analysis. Leukemia 1995; 9: 210–215.
Van Der Burg M, Beverloo HB, Langerak AW, Wijsman J, Van Drunen E, Slater R et al. Rapid and sensitive detection of all types of MLL gene translocations with a single FISH probe set. Leukemia 1999; 13: 2107–2113.
Rigby PW, Dieckmann M, Rhodes C, Berg P . Labeling deoxyribonucleic acid to high specific activity in vitro by nick translation with DNA polymerase I. J Mol Biol 1977; 113: 237–251.
Arnoldus EP, Wiegant J, Noordermeer IA, Wessels JW, Beverstock GC, Grosveld GC et al. Detection of the Philadelphia chromosome in interphase nuclei. Cytogenet Cell Genet 1990; 54: 108–111.
Den Boer ML, Zwaan CM, Pieters R, Kazemier KM, Rottier MM, Flens MJ et al. Optimal immunocytochemical and flow cytometric detection of P-gp, MRP and LRP in childhood acute lymphoblastic leukemia. Leukemia 1997; 11: 1078–1085.
Rots MG, Pieters R, Kaspers GJL, Van Zantwijk CH, Noordhuis P, Mauritz R et al. Differential methotrexate resistance in childhood T – versus common/preB – acute lymphoblastic leukemia can be measured by an in situ thymidylate synthase inhibition assay, but not by the MTT assay. Blood 1999; 93: 1067–1074.
Ramakers-van Woerden NL, Pieters R, Rots MG, Van Zantwijk CH, Noordhuis P, Beverloo BH et al. Infants with acute lymphoblastic leukemia: no evidence for high methotrexate resistance. Leukemia 2002; 16: 941–951.
Basso G, Rondelli R, Covezzoli A, Putti M . The role of immunophenotype in acute lymphoblastic leukemia of infant age. Leuk Lymphoma 1994; 15: 51–60.
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; 84: 570–573.
Hilden JM, Frestedt JL, Moore RO, Heerema NA, Arthur DC, Reaman GH et al. Molecular analysis of infant acute lymphoblastic leukemia – MLL gene rearrangement and reverse transcriptase-polymerase chain reaction for t(4-11)(q21-q23). Blood 1995; 86: 3876–3882.
Greaves MF . Infant leukaemia biology, aetiology and treatment. Leukemia 1996; 10: 372–377.
Heerema NA, Sather HN, Sensel MG, Liu-Mares W, Lange BJ, Bostrom BC et al. Association of chromosome arm 9p abnormalities with adverse risk in childhood acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood 1999; 94: 1537–1544.
Kumagai M, Manabe A, Pui CH, Behm FG, Raimondi SC, Hancock ML et al. Stroma-supported culture in childhood B-lineage acute lymphoblastic leukemia cells predicts treatment outcome. J Clin Invest 1996; 97: 755–760.
Kersey JH, Wang D, Oberto M . Resistance of t(4;11) (MLL-AF4 fusion gene) leukemias to stress-induced cell death: possible mechanism for extensive extramedullary accumulation of cells and poor prognosis. Leukemia 1998; 12: 1561–1564.
Kaspers GJL, Kardos G, Pieters R, Van Zantwijk CH, Klumper E, Hählen K et al. Different cellular drug resistance profiles in childhood lymphoblastic and non-lymphoblastic leukemia: a preliminary report. Leukemia 1994; 8: 1224–1229.
Haarman E, Zwaan CM, Pieters R, Hählen K, Van Wering ER, Van Der Does-Van Den Berg A et al. Relevance of the in vitro response to glucocorticoids of untreated pediatric acute myeloid leukemic blasts. Med Pediatr Oncol 2000; 35: 228.
Hongo T, Yajima S, Sakurai M, Horikoshi Y, Hanada R . In vitro drug sensitivity testing can predict induction failure and early relapse of childhood acute lymphoblastic leukemia. Blood 1997; 89: 2959–2965.
Pieters R, Huismans DR, Loonen AH, Hählen K, Van Der Does-Van Den Berg A, Van Wering ER et al. Relation of cellular drug resistance to long-term clinical outcome in childhood acute lymphoblastic leukaemia. Lancet 1991; 338: 399–403.
Kaspers GJL, Veerman AJP, Pieters R, Van Zantwijk CH, Smets LA, Van Wering ER et al. In vitro cellular drug resistance and prognosis in newly diagnosed childhood acute lymphoblastic leukemia. Blood 1997; 90: 2723–2729.
Den Boer ML, Pieters R, Kazemier KM, Harms DO, Janka-Schaub GE, Van Der Does-Van Den Berg A et al. Prognostic value of drug resistance profiles in childhood acute lymphoblastic leukemia. Br J Haematol 1998; 102: 275 O-1104..
Zwaan CM, Kaspers GJL, Pieters R, Huismans DR, Van Wering ER, Janka-Schaub GE et al. Circumvention of cytarabine resistance by 2-Chlorodeoxyadenosine in pediatric acute myeloid and acute lymphoid leukemia: an in vitro study. Blood 2000; 96: 307.
Silverman LB, Mclean TW, Gelber RD, Donnelly MJ, Gilliland DG, Tarbell NJ et al. Intensified therapy for infants with acute lymphoblastic leukemia: results from the Dana-Farber Cancer Institute Consortium. Cancer 1997; 80: 2285–2295.
Ludwig WD, Rieder H, Bartram CR, 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 GMALL 03/87 and 04/89. Blood 1998; 92: 1898–1909.
Acknowledgements
The Dutch Cancer Society is acknowledged for financially supporting this study (Grant VU95-921). HBB was supported by Grant 99-111 from the Association for International Cancer Research. Participation of the POG group was supported in part by Grants CA 32053 and CA 29139 from the USPHS. We thank the DCSLG for supplying material and relevant clinical information. We also thank the pediatric oncological centers participating in the DCLSG, the German COALL, the BFM, and POG study groups. Karyotyping of the Dutch patients was performed by members of the Netherlands Working party on Cancer Genetics and Cytogenetics (NWCGC) at regional cytogenetics centres, members of which were: CG Beverstock, H de France, A Geurts van Kessel, A Hagemeijer-Hausman, A Hamers, B de Jong, and RM Slater. For German childhood cases, karyotyping was performed in the Oncogenetic Laboratory, Children's Hospital, University of Giessen, Germany. Upstream and downstream cosmid probes for FISH detection of MLL rearrangements were kindly provided by Prof JJM van Dongen, Department of Immunology, Erasmus University Rotterdam. We gratefully acknowledge the statistical advice provided by Dr Bezemer (Vrije Universiteit).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ramakers-van Woerden, N., Beverloo, H., Veerman, A. et al. In vitro drug-resistance profile in infant acute lymphoblastic leukemia in relation to age, MLL rearrangements and immunophenotype. Leukemia 18, 521–529 (2004). https://doi.org/10.1038/sj.leu.2403253
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2403253
Keywords
This article is cited by
-
Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia
Nature Communications (2023)
-
Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response
Nature Medicine (2023)
-
Therapeutic implications of menin inhibition in acute leukemias
Leukemia (2021)
-
A human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program
Nature Communications (2021)
-
Umbilical cord blood transplantation can overcome the poor prognosis of KMT2A-MLLT3 acute myeloid leukemia and can lead to good GVHD-free/relapse-free survival
Annals of Hematology (2021)