Reduced folate carrier expression in acute lymphoblastic leukemia: a mechanism for ploidy but not lineage differences in methotrexate accumulation. 1999

V M Belkov, and E Y Krynetski, and J D Schuetz, and Y Yanishevski, and E Masson, and S Mathew, and S Raimondi, and C H Pui, and M V Relling, and W E Evans
St Jude Children's Research Hospital, Memphis, TN; and the University of Tennessee, Memphis, TN, USA.

Methotrexate (MTX) is one of the most active and widely used agents for the treatment of acute lymphoblastic leukemia (ALL). To elucidate the mechanism for higher accumulation of MTX polyglutamates (MTX-PG) in hyperdiploid ALL and lower accumulation in T-lineage ALL, expression of the reduced folate carrier (RFC) was assessed by reverse transcription-polymerase chain reaction in ALL blasts isolated from newly diagnosed patients. RFC expression exhibited a 60-fold range among 29 children, with significantly higher expression in hyperdiploid B-lineage ALL (median, 11.3) compared with nonhyperdiploid ALL (median, 2.1; P <.0006), but no significant difference between nonhyperdiploid B-lineage and T-lineage ALL. Furthermore, mRNA levels of RFC (mapped by FISH to chromosome 21) were significantly related to chromosome 21 copy number (P =.0013), with the highest expression in hyperdiploid ALL blasts with 4 copies of chromosome 21. To assess the functional significance of gene copy number, MTX-PG accumulation was compared in ALL blasts isolated from 121 patients treated with either low-dose MTX (LDMTX; n = 60) or high-dose MTX (HDMTX; n = 61). After LDMTX, MTX-PG accumulation was highest in hyperdiploid B-lineage ALL with 4 copies of chromosome 21 (P =.011), but MTX-PG accumulation was not significantly related to chromosome 21 copy number after HDMTX (P =.24). These data show higher RFC expression as a mechanism for greater MTX accumulation in hyperdiploid B-lineage ALL and indicate that lineage differences in MTX-PG accumulation are not due to lower RFC expression in T-lineage ALL.

UI MeSH Term Description Entries
D008565 Membrane Proteins Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. Cell Membrane Protein,Cell Membrane Proteins,Cell Surface Protein,Cell Surface Proteins,Integral Membrane Proteins,Membrane-Associated Protein,Surface Protein,Surface Proteins,Integral Membrane Protein,Membrane Protein,Membrane-Associated Proteins,Membrane Associated Protein,Membrane Associated Proteins,Membrane Protein, Cell,Membrane Protein, Integral,Membrane Proteins, Integral,Protein, Cell Membrane,Protein, Cell Surface,Protein, Integral Membrane,Protein, Membrane,Protein, Membrane-Associated,Protein, Surface,Proteins, Cell Membrane,Proteins, Cell Surface,Proteins, Integral Membrane,Proteins, Membrane,Proteins, Membrane-Associated,Proteins, Surface,Surface Protein, Cell
D008727 Methotrexate An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of TETRAHYDROFOLATE DEHYDROGENASE and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. Amethopterin,Methotrexate Hydrate,Methotrexate Sodium,Methotrexate, (D)-Isomer,Methotrexate, (DL)-Isomer,Methotrexate, Dicesium Salt,Methotrexate, Disodium Salt,Methotrexate, Sodium Salt,Mexate,Dicesium Salt Methotrexate,Hydrate, Methotrexate,Sodium, Methotrexate
D011003 Ploidies The degree of replication of the chromosome set in the karyotype. Ploidy
D011099 Polyglutamic Acid A peptide that is a homopolymer of glutamic acid. Polyglutamate
D002352 Carrier Proteins Proteins that bind or transport specific substances in the blood, within the cell, or across cell membranes. Binding Proteins,Carrier Protein,Transport Protein,Transport Proteins,Binding Protein,Protein, Carrier,Proteins, Carrier
D002648 Child A person 6 to 12 years of age. An individual 2 to 5 years old is CHILD, PRESCHOOL. Children
D002675 Child, Preschool A child between the ages of 2 and 5. Children, Preschool,Preschool Child,Preschool Children
D002891 Chromosomes, Human, Pair 21 A specific pair of GROUP G CHROMOSOMES of the human chromosome classification. Chromosome 21
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D054198 Precursor Cell Lymphoblastic Leukemia-Lymphoma A neoplasm characterized by abnormalities of the lymphoid cell precursors leading to excessive lymphoblasts in the marrow and other organs. It is the most common cancer in children and accounts for the vast majority of all childhood leukemias. Leukemia, Lymphoblastic,Leukemia, Lymphoid, Acute,Lymphoblastic Leukemia,Lymphoblastic Lymphoma,Lymphocytic Leukemia, Acute,Lymphoma, Lymphoblastic,ALL, Childhood,Acute Lymphoid Leukemia,Leukemia, Acute Lymphoblastic,Leukemia, Lymphoblastic, Acute,Leukemia, Lymphoblastic, Acute, L1,Leukemia, Lymphoblastic, Acute, L2,Leukemia, Lymphoblastic, Acute, Philadelphia-Positive,Leukemia, Lymphocytic, Acute,Leukemia, Lymphocytic, Acute, L1,Leukemia, Lymphocytic, Acute, L2,Lymphoblastic Leukemia, Acute,Lymphoblastic Leukemia, Acute, Adult,Lymphoblastic Leukemia, Acute, Childhood,Lymphoblastic Leukemia, Acute, L1,Lymphoblastic Leukemia, Acute, L2,Lymphocytic Leukemia, L1,Lymphocytic Leukemia, L2,Acute Lymphoblastic Leukemia,Acute Lymphocytic Leukemia,Childhood ALL,L1 Lymphocytic Leukemia,L2 Lymphocytic Leukemia,Leukemia, Acute Lymphocytic,Leukemia, Acute Lymphoid,Leukemia, L1 Lymphocytic,Leukemia, L2 Lymphocytic,Lymphoid Leukemia, Acute,Precursor Cell Lymphoblastic Leukemia Lymphoma

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