Paroxysmal nocturnal haemoglobinuria clones in patients with myelodysplastic syndromes

Iwanaga, Masako; Furukawa, Koichi; Amenomori, Tatsuhiko; Mori, Hiroyuki; Nakamura, Hideo; Fuchigami, Kengo; Kamihira, Shimeru; Nakakuma, Hideki; Tomonaga, Masao

doi:10.1046/j.1365-2141.1998.00794.x

Cited by 83 publications

(62 citation statements)

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“…[31][32][33] Of clinical note, blood cells with PNH phenotype (GPI-deficient or GPI Ϫ cells) are frequently detected in patients with BM failure syndromes such as aplastic anemia 34,35 and MDS. 13 As expected, some of the patients really develop hemolytic PNH. 35 The observations suggest that GPI Ϫ cells survive immune-mediated BM injury putatively caused by cytotoxic cells such as NK cells and CTLs (so-called immunoselection).…”

Section: Introductionmentioning

confidence: 96%

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Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP

Hanaoka

Kawaguchi

Horikawa

et al. 2006

Blood

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The mechanism by which paroxysmal nocturnal hemoglobinuria (PNH) clones expand is unknown. PNH clones harbor PIGA mutations and do not synthesize glycosylphosphatidylinositol (GPI), resulting in deficiency of GPI-linked membrane proteins. GPI-deficient blood cells often expand in patients with aplastic anemia who sustain immune-mediated marrow injury putatively induced by cytotoxic cells, hence suggesting that the injury allows PNH clones to expand selectively. We previously reported that leukemic K562 cells preferentially survived natural killer (NK) cell-mediated cytotoxicity in vitro when they acquired PIGA mutations. We herein show that the survival is ascribable to the deficiency of stress-inducible GPI-linked membrane proteins ULBP1 and ULBP2, which activate NK and T cells. The ULBPs were detected on GPI-expressing but not on GPI-deficient K562 cells. IntroductionParoxysmal nocturnal hemoglobinuria (PNH) is an acquired stem cell disorder of clonal nature characterized by intravascular hemolysis, venous thrombosis, bone marrow (BM) dysfunction, and infrequent development of leukemia. [1][2][3][4] In the last 2 decades, virtually the entire mechanism leading to PNH hemolysis has been elucidated. [5][6][7][8] PNH stem cells acquire PIGA mutations and do not generate glycosylphosphatidylinositol (GPI), resulting in a deficiency of a series of GPI-linked membrane proteins, including complement regulatory molecules such as decay-accelerating factor (DAF) and CD59. PNH cells are then vulnerable to autologous complement. For example, PNH erythrocytes undergo complement-mediated hemolysis. Soon after, the molecular events leading to clinically serious hemolytic precipitation induced by infection were clarified. 9 On the other hand, more than half of patients with PNH show various cytopenias and decreased CD34 ϩ hematopoietic cells. [1][2][3][4][10][11][12] PNH closely associates with aplastic anemia and myelodysplastic syndromes (MDSs) that share BM failure and development of leukemia. 1,12,13 It has been indicated that immune-mediated BM injury underlies at least a part of the diseases. 1,12 Indeed, immunosuppressive therapy ameliorates their marrow failure. 1,12,14,15 Of interest, combination therapy with antithymocyte globulin and cyclosporine A, these immunosuppressants having individual target spectra, 16,17 gives better results than therapy with each 1 of the 2 immunosuppressants. 12,18 In general, both cytotoxic T lymphocytes (CTLs) of adaptive immunity and natural killer (NK) cells of innate immunity operate in combination rather than independently. [19][20][21][22] It is then conceivable that both cytotoxic cells exert critical roles in BM injury, 12,[23][24][25][26] although real features of the autoimmunity have not been delineated.The marked progress in understanding of PNH pathophysiology evokes the next concern about the etiology of PNH, and the mechanisms of both selective expansion of PNH clones 27 and development of leukemia. 28 Above all, we have focused on the expansion of affected cells to mani...

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Section: Introductionmentioning

confidence: 96%

“…[1][2][3][4][10][11][12] PNH closely associates with aplastic anemia and myelodysplastic syndromes (MDSs) that share BM failure and development of leukemia. 1,12,13 It has been indicated that immune-mediated BM injury underlies at least a part of the diseases. 1,12 Indeed, immunosuppressive therapy ameliorates their marrow failure.…”

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confidence: 99%

Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP

Hanaoka

Kawaguchi

Horikawa

et al. 2006

Blood

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“…17 Since PNH clones have been identified in 10% to 25% of patients with a diagnosis of MDS, flow cytometry aiming to identify such clones is increasingly becoming part of the work up of MDS. [17][18][19] As in MDS, evolution of PNH to leukemia is possible (reviewed in Ref. 20), although with a much lower frequency.…”

Section: Introductionmentioning

confidence: 99%

Dynamics of hematopoiesis in paroxysmal nocturnal hemoglobinuria (PNH): no evidence for intrinsic growth advantage of PNH clones

et al. 2002

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PNH is characterized by expansion of one or more stem cell clones with a PIG-A mutation, which causes a severe deficiency in the expression of glycosylphosphatidylinositol (GPI)-anchored proteins. There is evidence that the expansion of PIG-A mutant clones is concomitant with negative selection against PIG-A wild-type stem cells by an aplastic marrow environment. We studied 36 patients longitudinally by serial flow cytometry, and we determined the proportion of PNH red cells and granulocytes over a period of 1-6 years. We observed expansion of the PNH blood cell population(s) (at a rate of over 5% per year) in 12 out of 36 patients; in all other patients the PNH cell population either regressed or remained stable. The dynamics of the PNH cell population could not be predicted by clinical or hematologic parameters at presentation. These data indicate that in most cases the PNH cell expansion has already run its course by the time of diagnosis. In addition, since in most cases no further expansion takes place, we can infer that the tendency to overgrow normal cells is not an intrinsic property of the PNH clone.

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“…4 Recently, several researchers reported that 15-88.6% of untreated and/or treated AA patients have GPIdeficient cells [5][6][7][8][9][10][11][12][13][14] as do 10-23% of MDS patients. 12,[15][16][17] The proportions of GPI-deficient cells in AA and MDS patients varied greatly (0.003-99%) and were usually lower than those in PNH patients. [5][6][7][8][9][10][11][12][13][14][15][16][17] In addition, PIG-A mutations have partially been reported in patients with AA, 11,18 AA/PNH, 3,19 and MDS.…”

Section: Introductionmentioning

confidence: 99%

“…12,[15][16][17] The proportions of GPI-deficient cells in AA and MDS patients varied greatly (0.003-99%) and were usually lower than those in PNH patients. [5][6][7][8][9][10][11][12][13][14][15][16][17] In addition, PIG-A mutations have partially been reported in patients with AA, 11,18 AA/PNH, 3,19 and MDS. 15,17 However, it could not be ruled out that these AA and MDS patients analyzed for PIG-A gene abnormality are actually PNH, because the AA and MDS patients had 2.4-28.5% and 1.19-22% of GPI-negative erythrocytes, respectively.…”

Section: Introductionmentioning

confidence: 99%

High frequency of several PIG-A mutations in patients with aplastic anemia and myelodysplastic syndrome

et al. 2006

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To clarify some characteristics of phosphatidylinositol glycanclass A gene (PIG-A) mutations in aplastic anemia (AA) and myelodysplastic syndrome (MDS) patients compared with those in paroxysmal nocturnal hemoglobinuria (PNH) patients, we investigated PIG-A mutations in CD59 À granulocytes and CD48 À monocytes from seven AA, eight MDS, and 11 PNH Japanese patients. The most frequent base or type abnormalities of the PIG-A gene in AA and MDS patients were base substitutions or missense mutations, respectively, and deletions or frameshift mutations, respectively, in PNH patients. Several PIG-A mutations, most of which were statistically minor, were found in glycosylphosphatidylinositol-negative cells from all AA and MDS patients but not from all PNH patients. However, the common PIG-A mutations during the clinical course between CD59 À granulocytes and/or CD48 À monocytes from each AA or MDS patient, except for Case 5, were not found. PIG-A mutations were different between the granulocytes and monocytes from five AA and five MDS patients. Our results indicate that there were some characteristics of PIG-A mutations in AA and MDS patients compared with PNH patients and that several minor PNH clones in these patients occurred at random during the clinical course. This partly explains the transformation of AA or MDS to PNH at intervals.

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Paroxysmal nocturnal haemoglobinuria clones in patients with myelodysplastic syndromes

Cited by 83 publications

References 49 publications

Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP

Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP

Dynamics of hematopoiesis in paroxysmal nocturnal hemoglobinuria (PNH): no evidence for intrinsic growth advantage of PNH clones

High frequency of several PIG-A mutations in patients with aplastic anemia and myelodysplastic syndrome

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