BMI-1 Is Highly Expressed in M0-Subtype Acute Myeloid Leukemia

Sawa, Masashi; Yamamoto, Kazuhito; Yokozawa, Toshiya; Kiyoi, Hitoshi; Hishida, Asahi; Kajiguchi, Tomohiro; Seto, Masao; Kohno, Akio; Kïtamura, Kazuo; Itoh, Yoshie; Asou, Norio; Hamajima, Nobuyuki; Emi, Nobuhiko; Naoe, Tomoki

doi:10.1532/ijh97.05013

Cited by 73 publications

(56 citation statements)

References 14 publications

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“…73 In a separate study, the same group found that such CTL responses were not limited to the immunodominant WT1 [126][127][128][129][130][131][132][133][134] epitope, but could also be directed against other HLA-A*0201-restricted WT1-derived epitopes (WT1 [37][38][39][40][41][42][43][44][45] , WT1 [187][188][189][190][191][192][193][194][195] and WT1 [235][236][237][238][239][240][241][242][243] ). 88 A similar observation was made regarding PRAME, which is known to contain at least four different HLA-A*0201-restricted epitopes that can be naturally recognized (PRA [100][101][102][103][104][105][106][107][108] , PRA 142-151 , PRA 300-309 and PRA [425][426][427][428][429]...…”

Section: Criterion 4: Immunogenicity Humoral and Cellular Immune Respmentioning

confidence: 54%

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

2012

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The graft-versus-leukemia effect of allogeneic hematopoietic stem cell transplantation (HSCT) has shown that the immune system is capable of eradicating acute myeloid leukemia (AML). This knowledge, along with the identification of the target antigens against which antileukemia immune responses are directed, has provided a strong impetus for the development of antigen-targeted immunotherapy of AML. The success of any antigen-specific immunotherapeutic strategy depends critically on the choice of target antigen. Ideal molecules for immune targeting in AML are those that are: (1) leukemia-specific; (2) expressed in most leukemic blasts including leukemic stem cells; (3) important for the leukemic phenotype; (4) immunogenic; and (5) clinically effective. In this review, we provide a comprehensive overview on AML-related tumor antigens and assess their applicability for immunotherapy against the five criteria outlined above. In this way, we aim to facilitate the selection of appropriate target antigens, a task that has become increasingly challenging given the large number of antigens identified and the rapid pace at which new targets are being discovered. The information provided in this review is intended to guide the rational design of future antigen-specific immunotherapy trials, which will hopefully lead to new antileukemia therapies with more selectivity and higher efficacy.

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Section: Criterion 4: Immunogenicity Humoral and Cellular Immune Respmentioning

confidence: 54%

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

2012

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“…37 Others have also reported that BMI1 expression is elevated in many hematologic malignancies. [38][39][40][41][42] New data may provide some important insights into the possible role of BMI1 in the development of leukemic transformation. In a mouse model in which coexpression of the oncogenes HOXA9 and MEIS1 resulted in a quick onset of myeloid leukemia, no disease was observed in secondary bmi-1-deficient recipients, 12 suggesting that BMI1 is essential for the maintenance of HOXA9-MEIS1 leukemic stem cells.…”

Section: Bmi1-induced Maintenance Of Human Hscs 2627mentioning

confidence: 99%

Long-term maintenance of human hematopoietic stem/progenitor cells by expression of BMI1

Rizo

Dontje²,

Vellenga

et al. 2008

Blood

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The polycomb group (PcG) gene BMI1 has been identified as one of the key epigenetic regulators of cell fates during different stages of development in multiple murine tissues. In a clinically relevant model, we demonstrate that enforced expression of BMI1 in cord blood CD34 ؉ cells results in long-term maintenance and self-renewal of human hematopoietic stem and progenitor cells. Longterm culture-initiating cell frequencies were increased upon stable expression of BMI1 and these cells engrafted more efficiently in NOD-SCID mice. Week 5 cobblestone area-forming cells (CAFCs) were replated to give rise to secondary CAFCs. Serial transplantation studies in NOD-SCID mice revealed that secondary engraftment was only achieved with cells overexpressing BMI1. Importantly, BMI1-transduced cells proliferated in stromafree cytokine-dependent cultures for more than 20 weeks, while a stable population of approximately 1% to 5% of CD34 ؉ cells was preserved that retained colonyforming capacity. Whereas control cells lost most of their NOD-SCID engraftment potential after 10 days of ex vivo culturing in absence of stroma, NOD-SCID multilineage engraftment was retained by overexpression of BMI1. Thus, our data indicate that self-renewal of human hematopoietic stem cells is enhanced by BMI1, and we classify BMI1 as an intrinsic regulator of human stem/progenitor cell self-renewal. IntroductionCellular memory induced by chromatin modifications can be maintained through subsequent cell divisions by the opposing effects of transcriptional activators of Trithorax (Trx) proteins and repressors of the polycomb proteins (PcG). 1 Two functionally different PcG complexes have been identified. Polycomb repressive complex (PRC) 2, also termed as "initiation" complex, consists of several subunits, including EED, SU(Z)12, and EZH2, functions as a histone methyltransferase that specifically trimethylates histone 3 on lysine residue 27 (H3K27) resulting in compaction of the chromatin and subsequent gene silencing. 2 PRC1 which is referred to as "maintenance" complex consists of various subunits, including BMI1, RING1A/B, CBX, MEL18, and MPH/ RAE28. 2 This complex does not possess methyltransferase activity itself, and the only observed enzymatic activity is ubiquitinylation of lysine 119 of H2A via its RING subdomains. 3 However, it has recently been demonstrated that DNA methyltransferase (Dnmt1) is required for proper assembly of PRC1 complex and that it can associate with BMI1 via Dmap1 and thus regulate DNA and histone methylation. 4,5 These observations suggest that not only PRC2, but also PRC1, might affect the epigenetic state of cells via methylation in a more direct fashion.Polycomb target genes were mapped in genome-wide screens in human embryonic fibroblasts, 6 murine embryonic stem cells, 7,8 and Drosophila melanogaster. 9,10 In embryonic fibroblasts, PRC1, PRC2, and H3K27-3me co-occupied genes that tend to be involved in embryonic development and cell fate decisions. 6 In ES cells, SU(Z)12, EED, and H3K27-3me co-occupied genes th...

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“…76 Overexpression of PRC1 complex components, such as BMI1, has been correlated with adverse outcomes in several hematopoietic malignancies. [77][78][79][80][81][82] However, little is known about the actual mechanisms involved, but with the advent of genome-wide studies this is likely to change in the near future.…”

Section: H3k27 Methylationmentioning

confidence: 99%