Loss of the GPI-anchor in B-lymphoblastic leukemia by epigenetic downregulation of PIGH expression.
Am J Hematol
; 94(1): 93-102, 2019 01.
Article
em En
| MEDLINE
| ID: mdl-30370942
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linfócitos B
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Regulação Leucêmica da Expressão Gênica
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Glicosilfosfatidilinositóis
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Metilação de DNA
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Inativação Gênica
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Leucemia-Linfoma Linfoblástico de Células Precursoras
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Antígeno CD52
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Proteínas de Membrana
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Proteínas de Neoplasias
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article