HLA class II haplotype and quantitation of WT1 RNA in Japanese patients with paroxysmal nocturnal hemoglobinuria

Shichishima, Tsutomu; Okamoto, Masatoshi; Ikeda, Kazuhiko; Kaneshige, Toshihiko; Sugiyama, Haruo; Terasawa, Takashi; Osumi, Kenji; Maruyama, Yukio

doi:10.1182/blood.v100.1.22

Cited by 46 publications

(25 citation statements)

References 61 publications

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“…Our total association results confirmed earlier findings of strong DRB1*15:01 and DQB1*06:02 allele associations with PNH (Lombardi et al 2008;Maciejewski et al 2001;Shichishima et al 2002).…”

Section: Discussionsupporting

confidence: 82%

“…In PNH patients an increased frequency of HLA-DR2 phenotype, DRB1*15:01 genotype and DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype have been revealed (Lombardi et al 2008;Maciejewski et al 2001;Shichishima et al 2002). In Italian and North American white PNH patients an increased frequency of the haplotype B*14:02-Cw*08:02 has been additionally suggested (Lombardi et al 2008;Maciejewski et al 2001).…”

Section: Introductionmentioning

confidence: 98%

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The Patterns of MHC Association in Aplastic and Non-aplastic Paroxysmal Nocturnal Hemoglobinuria

Nowak

Mika‐Witkowska

Mendek-Czajkowska

et al. 2011

Arch. Immunol. Ther. Exp.

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The deficiency of glycosyl-phosphatidylinositol (GPI)-anchored proteins in plasma membranes of PIG-A gene mutated hematopoietic stem cells (HSCs) is so far insufficient to explain the domination of paroxysmal nocturnal hemoglobinuria (PNH) clone over the normal HSC. We attempted to elucidate possible link between MHC and initial severe aplastic anemia (ISAA/PNH) type and non-aplastic (n/PNH) outcome of PNH. In 50 PNH patients assigned as ISAA/PNH (n = 13), n/PNH (n = 33) or nonassigned (n = 4) and 200 ethnically matched controls we analyzed MHC associations. Our data confirmed strong associations of DRB1*15:01 (RR = 3.51, p = 0.0011) and DQB1*06:02 (RR = 7.09, p = 0.000026) alleles, especially with n/PNH subtype. B*18:01 allele was associated with increased risk of ISAA/PNH subtype (RR = 5.25, p = 0.0028). We conclude that both class II and class I MHC alleles are associated with different subsets of PNH. Clonal selection of PIG-A mutated cells with cognate metabolic block is associated with MHC class II alleles DRB1*15:01 and DQB1*06:02 independent from initial severe AA clone selection. MHC class I molecule B*18:01 can additionally influence the domination of PNH clone in PNH subjects with initial severe aplastic anemia.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 98%

The Patterns of MHC Association in Aplastic and Non-aplastic Paroxysmal Nocturnal Hemoglobinuria

Nowak

Mika‐Witkowska

Mendek-Czajkowska

et al. 2011

Arch. Immunol. Ther. Exp.

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“…20,35 By contrast, WT1 expression has been described to be highly increased in most cases of acute myeloid and lymphoid leukemia, [17][18][19][20] in CML, 23 myelodysplastic syndromes, 18,36 and also in acquired hematological diseases like paroxysmal nocturnal hemoglobinuria. 37 In this prospective study, using a sensitive RQ-PCR approach, we have analyzed WT1 expression in a large series of HES/CEL and secondary hypereosinophilic patients from whom all the essential data to establish a correct Figure 4 Evaluation of WT1 transcript amount during follow-up of a FIP1L1-PDGFRa-positive patients treated with imatinib. After 3 months of therapy the patients achieved a complete molecular response; FIP1L1-PDGFRa was negative and WT1 returned within the normal range.…”

Section: Discussionmentioning

confidence: 99%

WT1 transcript amount discriminates secondary or reactive eosinophilia from idiopathic hypereosinophilic syndrome or chronic eosinophilic leukemia

et al. 2007

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Idiopathic hypereosinophilic syndromes (HES) comprise a spectrum of indolent to aggressive diseases characterized by persistent hypereosinophilia. Hypereosinophilia can result from the presence of a defect in the hematopoietic stem cell giving rise to eosinophilia, it can be present in many myeloproliferative disorders or alternatively it may be a reactive form, secondary to many clinical conditions. The hybrid gene FIP1L1-PDGRFa was identified in a subset of patients presenting with HES or chronic eosinophilic leukemia (CEL). In spite of this, the majority of HES patients do not present detectable molecular lesions and for many of them the diagnosis is based on exclusion criteria and sometimes it remains doubt. In this study we explored the possibility to distinguish between HES/ CEL and reactive hypereosinophilia based on WT1 transcript amount. For this purpose, 312 patients with hypereosinophilia were characterized at the molecular and cytogenetic level and analyzed for WT1 expression at diagnosis and during follow-up. This study clearly demonstrates that WT1 quantitative assessment allows to discriminate between HES/CEL and reactive eosinophilia and represents a useful tool for disease monitoring especially in the patients lacking a marker of clonality.

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“…40 A recent report indicated that mean WT1 RNA levels in PNH patients were much higher than that in normal controls or patients with aplastic anemia. 41 WT1 mutations have been reported in three series of MDS patients. A WT1 mutation was reported in 0/23 MDS patients, 1/28 patients with MDS or MDS-related AML (the one patient with a mutation had MDS-related AML), 1/17 with MDS-related AML, and in 1/6 cases of therapy-related AML.…”

Section: Wt1 Expression In Mdsmentioning

confidence: 95%

WT1 in acute leukemia, chronic myelogenous leukemia and myelodysplastic syndrome: therapeutic potential of WT1 targeted therapies

Rosenfeld¹,

2003

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Among clinicians, initial awareness of the Wilms' tumor gene was limited mostly to pediatric oncologists. Almost a decade ago, overexpression of Wilms' tumor 1 (WT1) was observed in adult acute leukemia. Subsequent studies indicated that WT1 overexpression occurs in most cases of acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS). Limited tissue expression of WT1 in adults suggests that WT1 can be a target for leukemia/MDS therapy. WT1 expression in stem/ progenitor cells remains unsettled. However, lack of progenitor cell suppression by WT1 antisense or WT1-specific cytotoxic T cells provide some assurance that WT1 expression in progenitor cells is minimal or absent. Immunotherapy-based WT1 approaches are furthest along in preclinical development. WT1-specific cytotoxic lymphocytes can be generated from normals and leukemic patients. In mice, WT1 vaccines elicit specific immune responses without evidence of tissue damage. In this paper, we review studies validating the immunogenicity of WT1 and propose that leukemia and MDS may be a good clinical model to test the efficacy of a WT1 vaccine.

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HLA class II haplotype and quantitation of WT1 RNA in Japanese patients with paroxysmal nocturnal hemoglobinuria

Cited by 46 publications

References 61 publications

The Patterns of MHC Association in Aplastic and Non-aplastic Paroxysmal Nocturnal Hemoglobinuria

The Patterns of MHC Association in Aplastic and Non-aplastic Paroxysmal Nocturnal Hemoglobinuria

WT1 transcript amount discriminates secondary or reactive eosinophilia from idiopathic hypereosinophilic syndrome or chronic eosinophilic leukemia

WT1 in acute leukemia, chronic myelogenous leukemia and myelodysplastic syndrome: therapeutic potential of WT1 targeted therapies

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