Stem Cell Research

Weissman, Irving L.

doi:10.1001/jama.294.11.1359

Cited by 135 publications

(36 citation statements)

References 84 publications

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“…We have previously proposed (19,(27)(28)(29)(30), and in some cases shown (23,31), that, in the progression of myelogenous leukemias (and by analogy many cancers), the self-renewing stem cell (here HSC) must be the first cell to sustain the genetic or epigenetic event that initiates the MPD, and in the myeloid lineage, only HSC self-renew (32, 33). However, it is possible that the first event, in some cases, Expression of JAK2 V617F in normal versus PV colonies.…”

Section: Discussionmentioning

confidence: 99%

“…In that view, successive clonal progeny from the altered HSC clone could accumulate progression events, so that at the end of the process, a multiply altered clone could enable poorly regulated self-renewal by turning on the hematopoietic self-renewal pathway(s) (19). A corollary of that hypothesis is that the initiating events in these MPDs that can progress to acute leukemias sustain the events in HSC.…”

Section: Discussionmentioning

confidence: 99%

“…Phenotypic analysis of cells with a HSC phenotype (CD34 ϩ CD38 Ϫ CD90 ϩ Lin Ϫ ) and progenitor populations was performed with the aid of FACS in PV and normal peripheral blood samples (19)(20)(21)(22)(23)(24). Analysis of early-phase PV patient samples (Table 1) revealed increased numbers of cells with a HSC phenotype (Fig.…”

Section: Pv Peripheral Blood Samples Have Increased Numbers Of Cells mentioning

confidence: 99%

“…In this study, we performed a targeted molecular analysis of cells with a hematopoietic stem cell (HSC) phenotype (CD34 ϩ CD38 Ϫ CD90 ϩ Lin Ϫ ) (19)(20)(21)(22) and myeloid progenitors (23,24) in PV patient samples to identify the hematopoietic progenitor compartment that harbors the JAK2 V617F mutation and their responses to a JAK2 inhibitor, AG490 (25,26).…”

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confidence: 99%

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The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation

Jamieson

Gotlib²,

Durocher

et al. 2006

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

271

222

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Although a large proportion of patients with polycythemia vera (PV) harbor a valine-to-phenylalanine mutation at amino acid 617 (V617F) in the JAK2 signaling molecule, the stage of hematopoiesis at which the mutation arises is unknown. Here we isolated and characterized hematopoietic stem cells (HSC) and myeloid progenitors from 16 PV patient samples and 14 normal individuals, testing whether the JAK2 mutation could be found at the level of stem or progenitor cells and whether the JAK2 V617F-positive cells had altered differentiation potential. In all PV samples analyzed, there were increased numbers of cells with a HSC phenotype (CD34 ؉ CD38 ؊ CD90 ؉ Lin ؊ ) compared with normal samples. Hematopoietic progenitor assays demonstrated that the differentiation potential of PV was already skewed toward the erythroid lineage at the HSC level. The JAK2 V617F mutation was detectable within HSC and their progeny in PV. Moreover, the aberrant erythroid potential of PV HSC was potently inhibited with a JAK2 inhibitor, AG490.JAK ͉ signaling ͉ progenitors ͉ cell fate ͉ mutant allele

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Pv Peripheral Blood Samples Have Increased Numbers Of Cells mentioning

confidence: 99%

mentioning

confidence: 99%

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The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation

Jamieson

Gotlib²,

Durocher

et al. 2006

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

271

222

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“…However, it is increasingly being recognized that tumor cell dissemination may also be a very early event during malignant progression, occurring before the detection of the tumor, that seeds the body with cryptic micrometastatic deposits (Bernards and Weinberg, 2002;van 't Veer et al, 2002). This results in an insidious population of dormant invasive or metastatic cells awaiting subsequent activation, acting, in a sense, as tumour-specific stem cells (Weissman, 2005). Given the critical importance of tumor cell invasion in cancer pathobiology, it is paramount that we understand the molecular mechanisms that regulate this complex phenotype.…”

Section: Introductionmentioning

confidence: 99%

Transcription factors control invasion: AP-1 the first among equals

et al. 2006

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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

362

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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Stem Cell Research

Cited by 135 publications

References 84 publications

The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation

The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation

Transcription factors control invasion: AP-1 the first among equals

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

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