title: In vitro drug-resistance profile in infant acute lymphoblastic leukemia in relation to age, MLL rearrangements and immunophenotype.
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.
authors.affiliation: VU University Medical Center, Department of Pediatric Hematology/Oncology, Amsterdam, The Netherlands.
authors.forename: N L
authors.initials: NL
authors.lastname: Ramakers-van Woerden
authors.forename: H B
authors.initials: HB
authors.lastname: Beverloo
authors.forename: A J P
authors.initials: AJ
authors.lastname: Veerman
authors.forename: B M
authors.initials: BM
authors.lastname: Camitta
authors.forename: A H
authors.initials: AH
authors.lastname: Loonen
authors.forename: E R
authors.initials: ER
authors.lastname: van Wering
authors.forename: R M
authors.initials: RM
authors.lastname: Slater
authors.forename: J
authors.initials: J
authors.lastname: Harbott
authors.forename: M L
authors.initials: ML
authors.lastname: den Boer
authors.forename: W D
authors.initials: WD
authors.lastname: Ludwig
authors.forename: O A
authors.initials: OA
authors.lastname: Haas
authors.forename: G E
authors.initials: GE
authors.lastname: Janka-Schaub
authors.forename: R
authors.initials: R
authors.lastname: Pieters
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D017677:Age Distribution; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D016130:Immunophenotyping; D066298:In Vitro Techniques; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051788:Myeloid-Lymphoid Leukemia Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011519:Proto-Oncogenes; D014157:Transcription Factors; D020394:Vault Ribonucleoprotein Particles / Q000378:metabolism; D000099187:Major Vault Protein
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D011495:Histone-Lysine N-Methyltransferase; D051788:Myeloid-Lymphoid Leukemia Protein; D009363:Neoplasm Proteins; D014157:Transcription Factors; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C497422:KMT2A protein, human