TY - JOUR
T1 - In vitro drug-resistance profile in infant acute lymphoblastic leukemia in relation to age, MLL rearrangements and immunophenotype
AU - Ramakers-van Woerden, N L
AU - Beverloo, H B
AU - Veerman, A J P
AU - Camitta, B M
AU - Loonen, A H
AU - van Wering, E R
AU - Slater, R M
AU - Harbott, J
AU - den Boer, M L
AU - Ludwig, W D
AU - Haas, O A
AU - Janka-Schaub, G E
AU - Pieters, R
N1 - Funding Information:
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).
PY - 2004/3
Y1 - 2004/3
N2 - 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.
AB - 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.
KW - ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
KW - Age Distribution
KW - Antineoplastic Agents/pharmacology
KW - DNA-Binding Proteins/genetics
KW - Drug Resistance, Neoplasm
KW - Drug Screening Assays, Antitumor
KW - Female
KW - Gene Rearrangement
KW - Histone-Lysine N-Methyltransferase
KW - Humans
KW - Immunophenotyping
KW - In Vitro Techniques
KW - Infant
KW - Infant, Newborn
KW - Male
KW - Myeloid-Lymphoid Leukemia Protein
KW - Neoplasm Proteins/metabolism
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
KW - Proto-Oncogenes
KW - Transcription Factors
KW - Vault Ribonucleoprotein Particles/metabolism
UR - https://www.scopus.com/pages/publications/1542608515
U2 - 10.1038/sj.leu.2403253
DO - 10.1038/sj.leu.2403253
M3 - Article
C2 - 14712291
SN - 0887-6924
VL - 18
SP - 521
EP - 529
JO - Leukemia
JF - Leukemia
IS - 3
ER -