AML xenograft efficiency is significantly improved in NOD/SCID-IL2RG mice constitutively expressing human SCF, GM-CSF and IL-3

Wunderlich, Mark; Fs, Chou; Ka, Link; Mizukawa, Benjamin; Perry, RH; Carroll, Martin; Mulloy, JC

doi:10.1038/leu.2010.158

Cited by 343 publications

(359 citation statements)

References 10 publications

Supporting

Mentioning

347

Contrasting

Order By: Relevance

“…Continued genetic modifications of candidate host mice will probably enable at least some of the species-specific needs to be addressed in the future. These include the possibility of creating transgenic mice that will express species-specific human cytokines, or the use of humanized mice (mice transplanted with human haematopoietic or local tissue components) to create more human-type microenvironments -as has proved useful for certain types of normal human cells [53][54][55][56][57] . Orthotopic injections of CSCs into various target organs may also prove useful, and mimicry of natural tumour immunosurveillance mechanisms may be achievable using injections of specific immune effector cells (TABLE 2).…”

Section: Csc Assays: Strengths and Caveatsmentioning

confidence: 99%

Cancer stem cell definitions and terminology: the devil is in the details

Valent

Bonnet

Maria³

et al. 2012

Nat Rev Cancer

621

564

View full text Add to dashboard Cite

| The cancer stem cell (CSC) concept has important therapeutic implications, but its investigation has been hampered both by a lack of consistency in the terms used for these cells and by how they are defined. Evidence of their heterogeneous origins, frequencies and their genomic, as well as their phenotypic and functional, properties has added to the confusion and has fuelled new ideas and controversies. Participants in The Year 2011 Working Conference on CSCs met to review these issues and to propose a conceptual and practical framework for CSC terminology. More precise reporting of the parameters that are used to identify CSCs and to attribute responses to them is also recommended as key to accelerating an understanding of their biology and developing more effective methods for their eradication in patients. PERSPECTIVES NATURE REVIEWS | CANCER VOLUME 12 | NOVEMBER 2012 | 767

show abstract

Section: Csc Assays: Strengths and Caveatsmentioning

confidence: 99%

Cancer stem cell definitions and terminology: the devil is in the details

Valent

Bonnet

Maria³

et al. 2012

Nat Rev Cancer

621

564

View full text Add to dashboard Cite

show abstract

“…MA9Ras cells express IL1RAP on the cell surface (Fig. 1A) and have been shown to faithfully recapitulate human AML in a xenograft setting (11). Untreated nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice engrafted with MA9Ras cells developed acute leukemia with a latency of 50-65 d and displayed high leukemic engraftment in bone marrow (BM) and spleen (Fig.…”

Section: Significancementioning

confidence: 99%

Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia

Ågerstam

Karlsson

Hansen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) is associated with a poor survival rate, and there is an urgent need for novel and more efficient therapies, ideally targeting AML stem cells that are essential for maintaining the disease. The interleukin 1 receptor accessory protein (IL1RAP; IL1R3) is expressed on candidate leukemic stem cells in the majority of AML patients, but not on normal hematopoietic stem cells. We show here that monoclonal antibodies targeting IL1RAP have strong antileukemic effects in xenograft models of human AML. We demonstrate that effector-cell-mediated killing is essential for the observed therapeutic effects and that natural killer cells constitute a critical human effector cell type. Because IL-1 signaling is important for the growth of AML cells, we generated an IL1RAP-targeting antibody capable of blocking IL-1 signaling and show that this antibody suppresses the proliferation of primary human AML cells. Hence, IL1RAP can be efficiently targeted with an anti-IL1RAP antibody capable of both achieving antibody-dependent cellular cytotoxicity and blocking of IL-1 signaling as modes of action. Collectively, these results provide important evidence in support of IL1RAP as a target for antibody-based treatment of AML.A cute myeloid leukemia (AML) is a genetically heterogeneous disease characterized by clonal expansion of leukemic cells. Despite an increased understanding of the underlying disease biology in AML, the standard treatment with cytotoxic chemotherapy has remained largely unchanged over the last decades and the overall 5-y survival remains poor, being <30% (1, 2). Hence, there is a pressing need for novel therapies with increased efficacy and decreased toxicity, ideally targeting the AML stem cells because these cells are believed to be critical in the pathogenesis of AML, and their inadequate eradication by standard therapy is thought to contribute to the high incidence of relapse (3, 4). Although therapeutic antibodies directed at cell-surface molecules have proven effective for the treatment of malignant disorders such as lymphomas and acute lymphoblastic leukemia, as well as solid tumors (5, 6), no antibody-based therapy is currently approved for AML.The interleukin 1 receptor accessory protein (IL1RAP), also called IL1R3, is a coreceptor of type 1 interleukin 1 receptor (IL1R1) and is indispensable for transmission of IL-1 signaling (7). We have previously reported that IL1RAP is a biomarker for putative chronic myeloid leukemia stem cells (8). In a recent study, we showed that IL1RAP is expressed on the cell surface in ∼80% of AML patients and that candidate CD34 + CD38 − AML stem cells can be selectively killed in vitro by antibody-dependent cellular cytotoxicity (ADCC) (9). Furthermore, IL1RAP is upregulated on immature cells in high-risk AML with chromosome 7 aberrations, and increased IL1RAP expression correlates with poor prognosis (10). These findings could suggest IL1RAP as a novel and specific target for an antibody-based therapy in AML; however, in vivo evidences for therapeuti...

show abstract

“…stem cell factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-3 (NSGS) as previously described (32). AE and AE9a showed comparable engraftment levels at 12 wk, with high variability and no apparent differences among the tested cultures (Fig.…”

Section: Significancementioning

confidence: 97%

Supraphysiologic levels of the AML1-ETO isoform AE9a are essential for transformation

Link

Lin

Shrestha

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Chromosomal translocation 8;21 is found in 40% of the FAB M2 subtype of acute myeloid leukemia (AML). The resultant in-frame fusion protein AML1-ETO (AE) acts as an initiating oncogene for leukemia development. AE immortalizes human CD34 + cord blood cells in longterm culture. We assessed the transforming properties of the alternatively spliced AE isoform AE9a (or alternative splicing at exon 9), which is fully transforming in a murine retroviral model, in human cord blood cells. Full activity was realized only upon increased fusion protein expression. This effect was recapitulated in the AE9a murine AML model. Cotransduction of AE and AE9a resulted in a strong selective pressure for AE-expressing cells. In the context of AE, AE9a did not show selection for increased expression, affirming observations of human t(8;21) patient samples where full-length AE is the dominant protein detected. Mechanistically, AE9a showed defective transcriptional regulation of AE target genes that was partially corrected at high expression. Together, these results bring an additional perspective to our understanding of AE function and highlight the contribution of oncogene expression level in t(8;21) experimental models.T he t(8;21)(q22;q22) chromosomal translocation comprises the N-terminal DNA binding domain of AML1 (RUNX1) and nearly the entire ETO (RUNX1T1) gene, forming the fusion protein AML1-ETO (AE) (1, 2). Conditional expression and transduction-transplantation approaches have demonstrated that expression of AE provides self-renewal signaling to hematopoietic stem/progenitor cells (HSPCs) but does not induce transformation in the absence of additional cooperating events (3-7). Several such cooperating events have been identified, including overexpression of WT1, mutant c-KIT, TEL-PDGFRB, FLT3-ITD, loss of p21, and treatment with the DNA-damaging agent ENU (6,(8)(9)(10)(11)(12)(13). Conversely, C-terminal truncation of AE through frameshift mutation (AML1-ETOtr) or alternative splicing at exon 9 (AE9a) leads to acute myeloid leukemia (AML) transformation of murine HSPCs (14, 15). The AE9a transcript is expressed in ∼70% of t(8;21) + AML patients, along with full-length AE (14, 16). AE9a lacks the conserved ETO domains NHR3/4, whose interaction with corepressor proteins such as N-CoR/SMRT and HDACs is important for transcriptional repression (17)(18)(19)(20). Despite maintaining some corepressor interaction, AE9a has greatly diminished N-CoR and SMRT interaction and is a much less potent transcriptional repressor than full-length AE (17,(19)(20)(21)(22). The AML1-ETOtr mutant showed altered regulation of cell cycle proteins, thereby providing a proliferative advantage in K562 cells relative to AE (15). Recently, DeKelver et al. showed that the interaction between N-CoR and the NHR4 domain plays an inhibitory role in leukemia development in the context of full-length AE (23). However, analysis of a small cohort of t(8;21) patient samples did not detect any mutations in the NHR4 domain, indicating that such mutations are probabl...

show abstract

AML xenograft efficiency is significantly improved in NOD/SCID-IL2RG mice constitutively expressing human SCF, GM-CSF and IL-3

Cited by 343 publications

References 10 publications

Cancer stem cell definitions and terminology: the devil is in the details

Cancer stem cell definitions and terminology: the devil is in the details

Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia

Supraphysiologic levels of the AML1-ETO isoform AE9a are essential for transformation

Contact Info

Product

Resources

About