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Loss of the GPI‐anchor in B‐lymphoblastic leukemia by epigenetic downregulation of PIGH expression
Author(s) -
Loeff Floris C.,
Rijs Kevin,
Egmond Esther H. M.,
Zoutman Willem H.,
Qiao Xiaohang,
Kroes Wilhelmina G. M.,
Veld Sabrina A. J.,
Griffioen Marieke,
Vermeer Maarten H.,
Neefjes Jacques,
Frederik Falkenburg J. H.,
Halkes Constantijn J. M.,
Jedema Inge
Publication year - 2019
Publication title -
american journal of hematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.456
H-Index - 105
eISSN - 1096-8652
pISSN - 0361-8609
DOI - 10.1002/ajh.25337
Subject(s) - cd52 , epigenetics , alemtuzumab , phenotype , gene silencing , cancer research , downregulation and upregulation , biology , immunology , b cell , mutation , chronic lymphocytic leukemia , leukemia , gene , medicine , genetics , antibody
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.