Abstract
Adult B-lymphoblastic leukemia (B-ALL) is a hematological malignancy characterized by genetic heterogeneity. Despite successful remission induction with classical chemotherapeutics and novel targeted agents, enduring remission is often hampered by disease relapse due to outgrowth of a pre-existing subclone resistant against the treatment. In this study, we show that small glycophosphatidylinositol (GPI)-anchor deficient CD52-negative B-cell populations are frequently present already at diagnosis in B-ALL patients, but not in patients suffering from other B-cell malignancies. We demonstrate that the GPI-anchor negative phenotype results from loss of mRNA expression of the PIGH gene, which is involved in the first step of GPI-anchor synthesis. Loss of PIGH mRNA expression within these B-ALL cells follows epigenetic silencing rather than gene mutation or deletion. The coinciding loss of CD52 membrane expression may contribute to the development of resistance to alemtuzumab (ALM) treatment in B-ALL patients resulting in the outgrowth of CD52-negative escape variants. Additional treatment with 5-aza-2'-deoxycytidine may restore expression of CD52 and revert ALM resistance.
© 2018 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alemtuzumab / therapeutic use
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Antimetabolites, Antineoplastic / pharmacology
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Antimetabolites, Antineoplastic / therapeutic use
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Antineoplastic Agents, Immunological / therapeutic use
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B-Lymphocytes / metabolism*
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B-Lymphocytes / pathology
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CD52 Antigen / biosynthesis
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CD52 Antigen / deficiency*
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CD52 Antigen / genetics
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Cell Line, Tumor
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DNA Methylation / drug effects*
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Decitabine / pharmacology
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Decitabine / therapeutic use
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Down-Regulation / drug effects
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Gene Expression Regulation, Leukemic* / drug effects
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Gene Silencing*
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Glycosylphosphatidylinositols / biosynthesis
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Glycosylphosphatidylinositols / deficiency*
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Glycosylphosphatidylinositols / genetics
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Humans
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Membrane Proteins / biosynthesis
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Membrane Proteins / genetics*
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / deficiency*
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Neoplasm Proteins / genetics
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Phenotype
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Neoplasm / biosynthesis
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RNA, Neoplasm / genetics
Substances
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Antimetabolites, Antineoplastic
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Antineoplastic Agents, Immunological
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CD52 Antigen
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CD52 protein, human
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Glycosylphosphatidylinositols
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Membrane Proteins
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Neoplasm Proteins
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PIGH protein, human
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RNA, Messenger
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RNA, Neoplasm
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Alemtuzumab
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Decitabine