Cellular drug sensitivity in MLL-rearranged childhood acute leukaemia is correlated to partner genes and cell lineage.
Rearrangements in the 11q23 region, the site of the mixed lineage leukaemia (MLL) gene, are found in both childhood acute myeloid (AML) and lymphoblastic (ALL) leukaemia. We studied the in vitro drug resistance by the fluorometric microculture cytotoxicity assay (FMCA) in 132 children with AML and 178 children with ALL (aged 0-17 years). In AML, children with t(9;11) (n = 10) were significantly more sensitive to cytarabine (P < 0.001) and doxorubicin (P = 0.005) than non-11q23 rearranged patients (n = 108). Children with other 11q23 rearrangements (n = 14) differed less from non-rearranged children. The 'AML-profile' common to all three groups included relative resistance to glucocorticoids and vincristine. In ALL, children with 11q23 rearrangement (n = 22) were significantly more sensitive to cytarabine (P = 0.026) than children without 11q23 rearrangement (n = 156), also after stratification for white blood cell count. In conclusion, the findings indicate that the cellular drug resistance is correlated to both the cell lineage and the type of 11q23 rearrangement. High cellular sensitivity to cytarabine and doxorubicin might explain the excellent treatment results in children with AML and t(9;11). The present study supports the strategy of contemporary protocols to include high-dose cytarabine in the treatment of 11q23-positive patients both in AML and ALL.
Palle
J
J
Department of Women's and Children's Health, University Children's Hospital, Uppsala, Sweden. josefine.palle@akademiska.se
Frost
B M
BM
Forestier
E
E
Gustafsson
G
G
Nygren
P
P
Hellebostad
M
M
Jonsson
O G
OG
Kanerva
J
J
Schmiegelow
K
K
Larsson
R
R
Lönnerholm
G
G
D000208:Acute Disease; D000293:Adolescent; D000970:Antineoplastic Agents / Q000494:pharmacology; D019070:Cell Lineage; D002648:Child; D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11; D002899:Chromosomes, Human, Pair 9; D003561:Cytarabine / Q000494:pharmacology; D003601:Cytotoxicity Tests, Immunologic; D004268:DNA-Binding Proteins / Q000235:genetics*; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005470:Fluorometry; D015321:Gene Rearrangement; D005938:Glucocorticoids / Q000494:pharmacology; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000276:immunology; D008297:Male; D051788:Myeloid-Lymphoid Leukemia Protein; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000276:immunology; D011446:Prospective Studies; D011519:Proto-Oncogenes / Q000235:genetics*; D018709:Statistics, Nonparametric; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; C497422:KMT2A protein, human; D014157:Transcription Factors; D003561:Cytarabine; D051788:Myeloid-Lymphoid Leukemia Protein; D004317:Doxorubicin; D011495:Histone-Lysine N-Methyltransferase