Dysregulated gene expression networks in human acute myelogenous leukemia stem cells

Majeti, Ravindra; Becker, Michael W.; Tian, Qiang; Lee, Tsung Lu Michael; Yan, Xiaowei; Li, Rui; Chiang, Jung-Hsien; Hood, Leroy; Clarke, Michael F.; Weissman, Irving L.

doi:10.1073/pnas.0900089106

Cited by 253 publications

(259 citation statements)

References 40 publications

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“…29 A similar observation was made by Gerber et al 30 for hTERT, proteinase 3 and survivin, which were shown to be downregulated in chronic myeloid leukemia (CML)-LSCs relative to normal HSCs. 30 Interestingly, in this study, conversion of chronic phase CML to blast crisis-which resembles AML-was paralleled by a further decrease in hTERT, proteinase 3 and survivin expression levels in the LSC compartment.…”

Section: Criterion 2: Frequency and Pattern Of Expressionsupporting

confidence: 62%

“…28 This explains the impetus behind latest efforts to better characterize LSCs and to unravel their gene expression profiles. Majeti et al 29 compared the gene expression signature of LSCs with that of normal HSCs and identified over 3000 genes with dysregulated expression in LSCs. 29 The published data set also includes several genes encoding proteins that can be recognized by the immune system and act as LAAs, such as Elicited (T) 47,95 Natural (B/T) 25 …”

Section: Criterion 2: Frequency and Pattern Of Expressionmentioning

confidence: 99%

“…As shown in Table 1, several of the hitherto described AML-related tumor antigens are present within the CD34 þ CD38 À leukemic cell compartment and may thus prove appropriate for LSC-directed therapy (for example, B lymphoma Mo-MLV insertion region 1 homolog (BMI1)). Selective overexpression in LSCs (that is, expression in LSCs with minimal or no expression in normal HSCs) has been demonstrated for Aurora A (AurA) kinase, 32 B-cell lymphoma protein-2 (Bcl-2), 29 cyclin A1, 29,33 mucin 1 (MUC1), 34 PRAME, 30 synovial sarcoma X breakpoint 2-interacting protein (SSX2IP) 29 and WT1 (Table 1). 29 The overexpression of WT1 in LSCs has been corroborated by Saito et al, 28 who demonstrated that WT1 was among the most frequently upregulated genes in AML-LSCs relative to normal HSCs.…”

Section: Criterion 2: Frequency and Pattern Of Expressionmentioning

confidence: 99%

“…Selective overexpression in LSCs (that is, expression in LSCs with minimal or no expression in normal HSCs) has been demonstrated for Aurora A (AurA) kinase, 32 B-cell lymphoma protein-2 (Bcl-2), 29 cyclin A1, 29,33 mucin 1 (MUC1), 34 PRAME, 30 synovial sarcoma X breakpoint 2-interacting protein (SSX2IP) 29 and WT1 (Table 1). 29 The overexpression of WT1 in LSCs has been corroborated by Saito et al, 28 who demonstrated that WT1 was among the most frequently upregulated genes in AML-LSCs relative to normal HSCs. 28 This is consistent with the observation that WT1-specific CTLs were capable of selectively eliminating leukemic cells while sparing normal marrow progenitors.…”

Section: Criterion 2: Frequency and Pattern Of Expressionmentioning

confidence: 99%

“…64 According to Greiner et al, 25 up to 70% of AML patients in complete remission spontaneously exhibit circulating PRA 300-309 -specific CTLs, further underscoring the significant natural immunogenicity of PRAME. 25 CD8 þ T cells specific for G250/CAIX [24][25][26][27][28][29][30][31][32] , G250/CAIX 254-262 and RHAMM [165][166][167][168][169][170][171][172][173] are also regularly detected in the peripheral blood of AML patients, with frequencies of 60%, 13% and 47%, respectively. 25 In a series of 15 AML patients, Siegel et al 22 observed spontaneous T-cell immune responses to different HLA-A*0201-restricted T-cell epitopes derived from OFA-iLRP, including iLR1 [59][60][61][62][63][64][65][66][67][68] (6/15) …”

Section: Criterion 4: Immunogenicity Humoral and Cellular Immune Respmentioning

confidence: 99%

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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 2: Frequency and Pattern Of Expressionsupporting

confidence: 62%

Section: Criterion 2: Frequency and Pattern Of Expressionmentioning

confidence: 99%

Section: Criterion 2: Frequency and Pattern Of Expressionmentioning

confidence: 99%

Section: Criterion 2: Frequency and Pattern Of Expressionmentioning

confidence: 99%

Section: Criterion 4: Immunogenicity Humoral and Cellular Immune Respmentioning

confidence: 99%

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

2012

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The Serotonin Transporter Promoter Variant (5-HTTLPR), Stress, and Depression Meta-analysis Revisited

Karg¹,

Burmeister²,

Shedden³

et al. 2011

Arch Gen Psychiatry

1,261

1,090

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Context The initial report of an interaction between a serotonin transporter promoter polymorphism (5-HTTLPR) and stress in the development of depression is perhaps the best-known and most cited finding in psychiatric genetics. Two recent meta-analyses explored the studies seeking to replicate this initial report and concluded that the evidence did not support the presence of the interaction. However, even the larger of the meta-analyses included only 14 of the 56 studies that have explored the relationship between 5-HTTLPR, stress and depression. Objective We sought to perform a meta-analysis including all relevant studies assessing whether 5-HTTLPR moderates the relationship between stress and depression. Data Sources We identified relevant articles from previous meta-analyses and reviews and a PubMed database search. Study Selection We excluded two studies presenting data that were included in other, larger, studies already included in our meta-analysis to avoid duplicate counting of subjects. Data Extraction In order to perform a more inclusive meta-analysis, we used the Liptak-Stouffer Z-score method to combine findings of primary studies at the significance test level rather than raw data level. Results We included 54 studies and found strong evidence that 5-HTTLPR moderates the relationship between stress and depression, with the 5-HTTLPR s allele associated with an increased risk of developing depression under stress (p<0.0001). When restricting our analysis to the studies included in the previous meta-analyses, we found no evidence of association (Munafo studies p=0.16; Risch studies p=0.11). This suggests that the difference in results between previous meta-analyses and ours was not due to the difference in meta-analytic technique but instead to the expanded set of studies included in this analysis. Conclusions Contrary to the results of the smaller earlier meta-analyses, we find strong evidence that 5-HTTLPR moderates the relationship between stress and depression in the studies published to date.

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Association of a Leukemic Stem Cell Gene Expression Signature With Clinical Outcomes in Acute Myeloid Leukemia

Gentles

Plevritis²,

Majeti³

et al. 2010

JAMA

363

317

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CUTE MYELOID LEUKEMIA(AML) is an aggressive malignancy of the bone marrow characterized by accumulation of early myeloid blood cells that fail to mature and differentiate. The course of the disease is marked by poor prognosis, frequent relapse, and high disease-related mortality. 1,2 Recent clinical investigation has focused on the identification of prognostic subgroups in adult AML with the goal of guiding patients into risk-adapted therapies. Such investigation determined that cytogenetic abnormalities are prognostic, some favorable and others unfavorable, 3,4 yet up to 50% of patients have normal karyotype AML with a wide range of clinical outcomes. In these patients, the presence of specific molecular mutations can provide prognostic information, including internal tandem duplications within the FLT3 gene, partial tandem duplication of the MLL gene, mislocalizing mutations of the NPM1 gene, mutations in the CEBPA and RAS genes, and increased expression of the BAALC and ERG genes. 5,6 However, these parameters and others such as patient age are only partially successful at capturing risk of relapse and patient outcomes following treatment.A growing body of evidence suggests that specific cancer cell subpopu-Context In many cancers, specific subpopulations of cells appear to be uniquely capable of initiating and maintaining tumors. The strongest support for this cancer stem cell model comes from transplantation assays in immunodeficient mice, which indicate that human acute myeloid leukemia (AML) is driven by self-renewing leukemic stem cells (LSCs). This model has significant implications for the development of novel therapies, but its clinical relevance has yet to be determined.Objective To identify an LSC gene expression signature and test its association with clinical outcomes in AML. Design, Setting, and PatientsRetrospective study of global gene expression (microarray) profiles of LSC-enriched subpopulations from primary AML and normal patient samples, which were obtained at a US medical center between April 2005 and July 2007, and validation data sets of global transcriptional profiles of AML tumors from 4 independent cohorts (n=1047). Main Outcome MeasuresIdentification of genes discriminating LSC-enriched populations from other subpopulations in AML tumors; and association of LSCspecific genes with overall, event-free, and relapse-free survival and with therapeutic response.Results Expression levels of 52 genes distinguished LSC-enriched populations from other subpopulations in cell-sorted AML samples. An LSC score summarizing expression of these genes in bulk primary AML tumor samples was associated with clinical outcomes in the 4 independent patient cohorts. High LSC scores were associated with worse overall, event-free, and relapse-free survival among patients with either normal karyotypes or chromosomal abnormalities. For the largest cohort of patients with normal karyotypes (n=163), the LSC score was significantly associated with overall survival as a continuous variable (hazard ratio [HR], 1.15; ...

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Dysregulated gene expression networks in human acute myelogenous leukemia stem cells

Cited by 253 publications

References 40 publications

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

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

The Serotonin Transporter Promoter Variant (5-HTTLPR), Stress, and Depression Meta-analysis Revisited

Association of a Leukemic Stem Cell Gene Expression Signature With Clinical Outcomes in Acute Myeloid Leukemia

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