Mutations in PIGA cause a CD52-/GPI-anchor-deficient phenotype complicating alemtuzumab treatment in T-cell prolymphocytic leukemia.
Alemtuzumab
/ pharmacology
CD52 Antigen
/ genetics
DNA Mutational Analysis
Gene Expression Regulation, Leukemic
/ drug effects
High-Throughput Nucleotide Sequencing
Humans
Immunophenotyping
Leukemia, Prolymphocytic, T-Cell
/ drug therapy
Membrane Proteins
/ genetics
Mutation
Phenotype
T-Lymphocytes
/ drug effects
CD52
PIGA
PNH
T-PLL
T-cell prolymphocytic leukemia
alemtuzumab
Journal
European journal of haematology
ISSN: 1600-0609
Titre abrégé: Eur J Haematol
Pays: England
ID NLM: 8703985
Informations de publication
Date de publication:
Dec 2020
Dec 2020
Historique:
received:
17
06
2020
revised:
24
08
2020
accepted:
24
08
2020
pubmed:
3
9
2020
medline:
30
7
2021
entrez:
3
9
2020
Statut:
ppublish
Résumé
Infusional alemtuzumab followed by consolidating allogeneic hematopoietic stem cell transplantation in eligible patients is considered a standard of care in T-cell prolymphocytic leukemia (T-PLL). Antibody selection against CD52 has been associated with the development of CD52-negative leukemic T cells at time of relapse. Clinical implications and molecular mechanisms underlying this phenotypic switch are unknown. We performed flow cytometry and real-time-PCR for CD52-expression and next generation sequencing for PIGA mutational analyses. We identified loss of CD52 expression after alemtuzumab treatment in two of 21 T-PLL patients resulting from loss of GPI-anchor expression caused by inactivating mutations of the PIGA gene. One patient with relapsed T-PLL exhibited a single PIGA mutation, causing a CD52-negative escape variant of the initial leukemic cell clone, preventing alemtuzumab-retreatment. The second patient with continued complete remission after alemtuzumab treatment harbored three different PIGA mutations that affected either the non-neoplastic T cell or the mononuclear cell compartment and resulted in symptomatic paroxysmal nocturnal hemoglobinuria. Next generation sequencing of T-PLL cells collected before the initiation of treatment revealed PIGA wild-type sequence reads in all 16 patients with samples available for testing. These data indicate that PIGA mutations were acquired during or after completion of alemtuzumab treatment.
Substances chimiques
CD52 Antigen
0
CD52 protein, human
0
Membrane Proteins
0
phosphatidylinositol glycan-class A protein
0
Alemtuzumab
3A189DH42V
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
786-796Informations de copyright
© 2020 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.
Références
Braun T, von Jan J, Wahnschaffe L, Herling M. Advances and perspectives in the treatment of T-PLL. Curr Hematol Malig Rep. 2020;15(2):113-124.
Wiktor-Jedrzejczak W, Drozd-Sokolowska J, Eikema DJ, et al. EBMT prospective observational study on allogeneic hematopoietic stem cell transplantation in T-prolymphocytic leukemia (T-PLL). Bone Marrow Transplant. 2019;54(9):1391-1398.
Dearden C. Management of prolymphocytic leukemia. Hematology. 2015;2015:361-367.
Shumilov E, Hasenkamp J, Szuszies CJ, Koch R, Wulf GG. Patterns of late relapse after allogeneic hematopoietic stem cell transplantation in patients with T-cell prolymphocytic leukemia. Acta Haematol. 2020;1-6. https://doi.org/10.1159/000506302
Damlaj M, Sulai NH, Oliveira JL, et al. Impact of alemtuzumab therapy and route of administration in T-prolymphocytic leukemia: a single-center experience. Clin Lymphoma Myeloma Leuk. 2015;15(11):699-704.
Birhiray RE, Shaw G, Guldan S, et al. Phenotypic transformation of CD52(pos) to CD52(neg) leukemic T cells as a mechanism for resistance to CAMPATH-1H. Leukemia. 2002;16(5):861-864.
Tuset E, Matutes E, Brito-Babapulle V, Morilla R, Catovsky D. Immunophenotype changes and loss of CD52 expression in two patients with relapsed T-cell prolymphocytic leukaemia. Leuk Lymphoma. 2001;42(6):1379-1383.
Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edn. LyonIARC Press; 2008.
Johansson P, Klein-Hitpass L, Choidas A, et al. SAMHD1 is recurrently mutated in T-cell prolymphocytic leukemia. Blood Cancer J. 2018;8(1):11.
Sutherland DR, Kuek N, Davidson J, et al. Diagnosing PNH with FLAER and multiparameter flow cytometry. Cytometry B Clin Cytom. 2007;72(3):167-177.
Untergasser A, Cutcutache I, Koressaar T, et al. Primer3-new capabilities and interfaces. Nucleic Acids Res. 2012;40(15):e115.
Leitao E, Beygo J, Zeschnigk M, et al. Locus-specific DNA methylation analysis by targeted deep bisulfite sequencing. Methods Mol Biol. 2018;1767:351-366.
Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25(14):1754-1760.
Li H, Handsaker B, Wysoker A, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25(16):2078-2079.
Nicol JW, Helt GA, Blanchard SG Jr, Raja A, Loraine AE. The Integrated Genome Browser: free software for distribution and exploration of genome-scale datasets. Bioinformatics. 2009;25(20):2730-2731.
Larkin MA, Blackshields G, Brown NP, et al. Clustal W and Clustal X version 2.0. Bioinformatics. 2007;23(21):2947-2948.
Xia MQ, Hale G, Lifely MR, et al. Structure of the CAMPATH-1 antigen, a glycosylphosphatidylinositol-anchored glycoprotein which is an exceptionally good target for complement lysis. Biochem J. 1993;293(Pt 3):633-640.
Lima M. Laboratory studies for paroxysmal nocturnal hemoglobinuria, with emphasis on flow cytometry. Pract Lab Med. 2020;20:e00158.
Loeff FC, Falkenburg JHF, Hageman L, et al. High mutation frequency of the PIGA gene in T cells results in reconstitution of GPI anchor(-)/CD52(-) T cells that can give early immune protection after alemtuzumab-based T cell-depleted allogeneic stem cell transplantation. J Immunol. 2018;200(6):2199-2208.
Rawstron AC, Rollinson SJ, Richards S, et al. The PNH phenotype cells that emerge in most patients after CAMPATH-1H therapy are present prior to treatment. Br J Haematol. 1999;107(1):148-153.
Kornauth CF, Herbaux C, Boidol B, et al. The combination of venetoclax and ibrutinib is effective in relapsed/refractory T-Prolymphocytic leukemia and influences BCL2- family member dependencies. Hematol Oncol. 2019;37(S2):482-484.
Roth A, Hock C, Konik A, Christoph S, Duhrsen U. Chronic treatment of paroxysmal nocturnal hemoglobinuria patients with eculizumab: safety, efficacy, and unexpected laboratory phenomena. Int J Hematol. 2011;93(6):704-714.
Rao SP, Sancho J, Campos-Rivera J, et al. Human peripheral blood mononuclear cells exhibit heterogeneous CD52 expression levels and show differential sensitivity to alemtuzumab mediated cytolysis. PLoS One. 2012;7(6):e39416.
Garland RJ, Groves SJ, Diamanti P, et al. Early emergence of PNH-like T cells after allogeneic stem cell transplants utilising CAMPATH-1H for T cell depletion. Bone Marrow Transplant. 2005;36(3):237-244.
Meyer RG, Wagner EM, Konur A, et al. Donor CD4 T cells convert mixed to full donor T-cell chimerism and replenish the CD52-positive T-cell pool after alemtuzumab-based T-cell-depleted allo-transplantation. Bone Marrow Transplant. 2010;45(4):668-674.
Hertenstein B, Wagner B, Bunjes D, et al. Emergence of CD52-, phosphatidylinositolglycan-anchor-deficient T lymphocytes after in vivo application of Campath-1H for refractory B-cell non-Hodgkin lymphoma. Blood. 1995;86(4):1487-1492.
Brett SJ, Baxter G, Cooper H, et al. Emergence of CD52-, glycosylphosphatidylinositol-anchor-deficient lymphocytes in rheumatoid arthritis patients following Campath-1H treatment. Int Immunol. 1996;8(3):325-334.
Fracchiolla NS, Barcellini W, Bianchi P, Motta M, Fermo E, Cortelezzi A. Biological and molecular characterization of PNH-like lymphocytes emerging after Campath-1H therapy. Br J Haematol. 2001;112(4):969-971.
Hill A, DeZern AE, Kinoshita T, Brodsky RA. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primers. 2017;3:17028.
Araten DJ, Nafa K, Pakdeesuwan K, Luzzatto L. Clonal populations of hematopoietic cells with paroxysmal nocturnal hemoglobinuria genotype and phenotype are present in normal individuals. Proc Natl Acad Sci USA. 1999;96(9):5209-5214.
Hu R, Mukhina GL, Piantadosi S, Barber JP, Jones RJ, Brodsky RA. PIG-A mutations in normal hematopoiesis. Blood. 2005;105(10):3848-3854.
Schrader A, Crispatzu G, Oberbeck S, et al. Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL. Nat Commun. 2018;9(1):697.
Kiel MJ, Velusamy T, Rolland D, et al. Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia. Blood. 2014;124(9):1460-1472.
Young NS, Maciejewski JP. Genetic and environmental effects in paroxysmal nocturnal hemoglobinuria: this little PIG-A goes "Why? Why? Why?". J Clin Invest. 2000;106(5):637-641.
Kinoshita T, Inoue N. Relationship between aplastic anemia and paroxysmal nocturnal hemoglobinuria. Int J Hematol. 2002;75(2):117-122.
Cheng KL, Brody J, Warshall CE, Sloand EM, Allen SL. Paroxysmal nocturnal hemoglobinuria following alemtuzumab immunosuppressive therapy for myelodysplastic syndrome and complicated by recurrent life-threatening thrombosis despite anticoagulation: successful intervention with eculizumab and fondaparinux. Leuk Res. 2010;34(4):e85-e87 e87.