MOLECULAR CORRELATES OF METHOTREXATE IN CHILDHOOD ALL

Summary

Principal Investigator: Larry Matherly
Abstract: [unreadable] DESCRIPTION (provided by applicant): This project is the result of a long-term collaboration between the principal investigator, a basic scientist, and physician scientists and is designed to identify determinants of treatment response in childhood acute lymphoblastic leukemia (ALL). The focus is on methotrexate (MTX) and 6-mercaptopurine (6-MP), antimetabolites that continue to be cornerstones of modern treatment protocols for ALL, and on critical unanswered questions relating to the effective clinical use of these agents. While major progress has been made in treating childhood ALL, this, in part, reflects subgroups comprising nearly 50% of patients with uniquely good prognoses. However, success in the treatment of other patients has lagged behind. We previously demonstrated: (a) a extraordinarily wide range (88-fold) of expression of the human reduced folate carrier (hRFC), the membrane transport system for MTX and tetrahydrofolates, in ALL lymphoblasts, and often disproportionate to levels of MTX transport (b) elevated hRFC expression in good prognosis ALL phenotypes, including hyperdiploidy and t(12;21); and (e) altered hRFC mRNA splice forms, gene sequence variants in the hRFC coding sequence, and a high frequency sequence deletion in a hRFC promoter. Studies were initiated to explore the contributions of (d) the high frequency C677T single nucleotide polymorphism in the methylene tetrahydrofolate reductase (MTHFR) gene and (e) the family of multidrug resistance proteins (MRPs) to chemotherapy response and resistance in pediatric ALLs. In this application, we propose to use primary ALL specimens and ALL xenografts engrafted in NOD-SCID mice to systematically establish: (i) the relationships between patterns of hRFC expression and MTX transport and sensitivities; (ii) the molecular mechanisms that result in the wide range of hRFC expression in primary specimens from the major hRFC-B promoter by in vitro and in vivo assays; (iii) the roles of gene and transcript sequence variants for hRFC and MTHFR as determinants of MTX response and resistance by high-throughput screening of ALL and non-ALL specimens and functional analysis in transfected cells; and (iv) the roles of the MRPs as determinants of MTX and 6-MP accumulations and sensitivities in ALL and transfected cells. Our results should foster the rational chemotherapy of childhood ALL by identifying patients most likely to respond to antimetabolite treatments, and/or who are likely to experience excessive toxicities. Our studies should also lead to new ALL therapies and be relevant to other malignant and non-malignant diseases treated with antifolate drugs. From the key role of hRFC in folate accumulations in mammalian cells and the potential contributions of folate deficiencies to chromosomal instability and malignant transformation, cardiovascular disease, and fetal abnormalities, our results should have far-reaching significance to human heath and disease.
Funding Period: 1998-01-01 - 2008-12-31
more information: NIH RePORT

Top Publications

  1. ncbi Transcriptional regulation of the human reduced folate carrier in childhood acute lymphoblastic leukemia cells
    Mingjun Liu
    Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, 110 East Warren Avenue, Detroit, MI 48201, USA
    Clin Cancer Res 12:608-16. 2006
  2. ncbi The GATA site-dependent hemogen promoter is transcriptionally regulated by GATA1 in hematopoietic and leukemia cells
    L V Yang
    Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA
    Leukemia 20:417-25. 2006
  3. ncbi Prognostic role of the reduced folate carrier, the major membrane transporter for methotrexate, in childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group
    Yubin Ge
    Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, 110 East Warren Avenue, Detroit, MI 48201, USA
    Clin Cancer Res 13:451-7. 2007
  4. ncbi Human reduced folate carrier: translation of basic biology to cancer etiology and therapy
    Larry H Matherly
    Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, The Cancer Biology Graduate Program, Detroit, MI 48201, USA
    Cancer Metastasis Rev 26:111-28. 2007
  5. pmc Identification and characterization of novel AML1-ETO fusion transcripts in pediatric t(8;21) acute myeloid leukemia: a report from the Children's Oncology Group
    K M LaFiura
    Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
    Oncogene 27:4933-42. 2008
  6. pmc The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group
    A Larson Gedman
    Graduate Program in Cancer Biology, Wayne State University School of Medicine, Detroit, MI, USA
    Leukemia 23:1417-25. 2009
  7. pmc Acute T-cell leukemias remain dependent on Notch signaling despite PTEN and INK4A/ARF loss
    Hind Medyouf
    Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC
    Blood 115:1175-84. 2010

Scientific Experts

  • Larry H Matherly
  • J W Taub
  • Y Ge
  • Yubin Ge
  • Mingjun Liu
  • Hind Medyouf
  • A Larson Gedman
  • K M LaFiura
  • Jeffrey W Taub
  • L V Yang
  • Francoise Pflumio
  • Qing Liu
  • Andrew P Weng
  • Mingjian James You
  • Xiuhua Gao
  • Florence Armstrong
  • Amanda Larson Gedman
  • Kirk R Schultz
  • Samuel Gusscott
  • C L Haska
  • C Cherian
  • S Kugel Desmoulin
  • Q Chen
  • K LaFiura
  • M Devidas
  • S B Linda
  • Y Ravindranath
  • H Edwards
  • J A Fontana
  • A N Mohamed
  • Katherine LaFiura
  • Ronald Thomas
  • Christina L Haska
  • Meenakshi Devidas
  • Stephen B Linda
  • S Y Kim
  • J Eliason
  • Y Fujiwara
  • Robin M Flatley
  • Z Fu
  • Ramzi Mohammad
  • Amro Aboukameel
  • Stephen Buck
  • J Wan
  • Scott G Payton
  • L Li
  • Christina Haska

Detail Information

Publications7

  1. ncbi Transcriptional regulation of the human reduced folate carrier in childhood acute lymphoblastic leukemia cells
    Mingjun Liu
    Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, 110 East Warren Avenue, Detroit, MI 48201, USA
    Clin Cancer Res 12:608-16. 2006
    ..The hRFC gene is regulated by six noncoding exons (A1/A2 and A to E) and multiple promoters. In ALL, hRFC-A1/A2 and hRFC-B are the major transcript forms...
  2. ncbi The GATA site-dependent hemogen promoter is transcriptionally regulated by GATA1 in hematopoietic and leukemia cells
    L V Yang
    Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA
    Leukemia 20:417-25. 2006
    ..This study suggests that the Hemgn promoter contains critical regulatory elements for its transcription in hematopoietic tissues and Hemgn is a direct target of GATA1 in leukemia cells...
  3. ncbi Prognostic role of the reduced folate carrier, the major membrane transporter for methotrexate, in childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group
    Yubin Ge
    Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, 110 East Warren Avenue, Detroit, MI 48201, USA
    Clin Cancer Res 13:451-7. 2007
    ....
  4. ncbi Human reduced folate carrier: translation of basic biology to cancer etiology and therapy
    Larry H Matherly
    Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, The Cancer Biology Graduate Program, Detroit, MI 48201, USA
    Cancer Metastasis Rev 26:111-28. 2007
    ..Many of the advances in the basic biology of RFC in cell line models are now being directly applied to human cancers in the clinical setting, most notably pediatric acute lymphoblastic leukemia and osteogenic sarcoma...
  5. pmc Identification and characterization of novel AML1-ETO fusion transcripts in pediatric t(8;21) acute myeloid leukemia: a report from the Children's Oncology Group
    K M LaFiura
    Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
    Oncogene 27:4933-42. 2008
    ....
  6. pmc The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group
    A Larson Gedman
    Graduate Program in Cancer Biology, Wayne State University School of Medicine, Detroit, MI, USA
    Leukemia 23:1417-25. 2009
    ....
  7. pmc Acute T-cell leukemias remain dependent on Notch signaling despite PTEN and INK4A/ARF loss
    Hind Medyouf
    Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC
    Blood 115:1175-84. 2010
    ..Thus, in contrast to previous findings with established cell lines, these results indicate PTEN loss does not relieve primary T-ALL cells of their "addiction" to Notch signaling...