Project description:Genome-wide assessment of gene expression in primary acute lymphoblastic leukemia cells was performed to identify genomic determinants of MTX’s antileukemic effects. Reduction of circulating leukemia cells after in vivo methotrexate treatment served as a measure MTX's antileukemic effects. Keywords: gene expression associated with drug response
Project description:Genome-wide assessment of gene expression in primary acute lymphoblastic leukemia cells was performed to identify genomic determinants of MTXâs antileukemic effects. Reduction of circulating leukemia cells after in vivo methotrexate treatment served as a measure MTX's antileukemic effects. Experiment Overall Design: Gene expression in diagnostic primary acute lymphoblastic leukemia cells from bone marrow of 161 pediatric patients
Project description:Treatment and prophylaxis of the central nervous system (CNS) is a critical component of acute lymphoblastic leukemia (ALL) therapy. However, CNS-directed therapies are a significant cause of morbidity and CNS relapse remains a cause of treatment failure. CNS-directed ALL therapies must target leukemia cells within cerebrospinal fluid (CSF), a fluid that is compositionally distinct from plasma and has been shown to impact leukemia biology. Herein, we demonstrate that human CSF attenuates the potency and efficacy of anti-folate drugs including methotrexate, the primary CNS-directed chemotherapeutic for over six decades. Importantly, this effect of CSF on leukemia methotrexate sensitivity was reversible. Additional mechanistic studies support that diminished proliferation and activation of the integrated stress response (ISR) in leukemia cells in CSF contribute to this resistance. Our findings suggest potential strategies to enhance methotrexate efficacy in CNS-directed ALL therapy and highlight the need to critically reassess even established standards of care.
Project description:To elucidate the genomics of cellular responses to cancer treatment, we analyzed the expression of over 9,600 human genes in acute lymphoblastic leukemia cells before and after in vivo treatment with methotrexate and mercaptopurine given alone or in combination. Based on changes in gene expression, we identified 124 genes that accurately discriminated among the four treatments. Discriminating genes included those involved in apoptosis, mismatch repair, cell cycle control and stress response. Only 14% of genes that changed when these medications were given as single agents also changed when they were given together. These data indicate that lymphoid leukemia cells of different molecular subtypes share common pathways of genomic response to the same treatment, that changes in gene expression are treatment-specific and that gene expression can illuminate differences in cellular response to drug combinations versus single agents.
Project description:Adipocyte conditioned media (ACM), stromal cell conditioned media (SCM) and unconditioned media (UCM) were added to B-cell Acute Lymphoblastic Leukemia cells (REH and RCH-AcV) either with or without methotrexate (MTX). The metabolomic profiles of the cells was determined by mass spectrometry.
