Introduction: spatial origin of murine hematopoietic stem cells

Yöder, Mervin C.

doi:10.1182/blood.v98.1.3

Cited by 31 publications

(15 citation statements)

References 39 publications

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“…The first signs of hematopoiesis in the developing mouse embryos are the formation of blood islands from extraembryonic mesoderm in the yolk sac at embryonic day 7.5 (E7.5) (Yoder, 2001). Blood islands are composed of primitive, nucleated erythrocytes surrounded by ECs.…”

Section: Smad Signaling and Specification Of Hscs During Developmentmentioning

confidence: 99%

The role of Smad signaling in hematopoiesis

2005

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Section: Smad Signaling and Specification Of Hscs During Developmentmentioning

confidence: 99%

The role of Smad signaling in hematopoiesis

2005

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“…WT carrier bone marrow hematopoietic cells were used to help reconstitute the hematopoietic system, because yolk sac stage hematopoietic precursor cells are not able to repopulate the hematopoietic system of adult recipient mice. 45,46 Because availability of yolk sac cells was limited, 5 recipient mice were used for each group in 2 independent experiments. Recipient mice were monitored for 6 months.…”

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confidence: 99%

SHP-2 phosphatase is required for hematopoietic cell transformation by Bcr-Abl

Chen

Daino

et al. 2006

Blood

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SHP-2 phosphatase forms a stable protein complex with and is heavily tyrosine-phosphorylated by the oncogenic tyrosine kinase Bcr-Abl. However, the role of SHP-2 in Bcr-Abl-mediated leukemogenesis is unclear. In the present report, we provide evidence that SHP-2 is required for hematopoietic cell transformation by Bcr-Abl. In vitro biological effects of Bcr-Abl transduction were diminished in SHP-2 ⌬/⌬ hematopoietic cells, and the leukemic potential of Bcr-Abltransduced SHP-2 ⌬/⌬ cells in recipient animals was compromised. Further analyses showed that Bcr-Abl protein (p210) was degraded, and its oncogenic signaling was greatly decreased in SHP-2 ⌬/⌬ cells. Treatment with proteasome inhibitors or reintroduction of SHP-2 restored p210 level in Bcr-Abl-transduced SHP-2 ⌬/⌬ cells. Subsequent investigation revealed that SHP-2 interacted with heat shock protein 90, an important chaperone protein protecting p210 from proteasome-mediated degradation. The role of SHP-2 in the stability of p210 is independent of its catalytic activity. Blockade of SHP-2 expression in p210-expressing cells by antisense or small-interfering RNA approaches decreased p210 level, causing cell death. Inhibition of SHP-2 enzymatic activity by overexpression of catalytically inactive SHP-2 mutant did not destabilize p210 but enhanced serum starvationinduced apoptosis, suggesting that SHP-2 also plays an important role in downstream signaling of p210 kinase. These studies identified a novel function of SHP-2 and suggest that SHP-2 might be a useful target for controlling Bcr-Abl-positive leukemias. IntroductionChronic myeloid leukemia (CML) is a clonal hematopoietic cell malignancy associated with the reciprocal t(9;22)(q34;q11) chromosome translocation. 1,2 Translocation of c-Abl located on chromosome 9 to the breakpoint-cluster region (Bcr) on chromosome 22 generates a fusion oncogene Bcr-Abl, which primarily produces the chimeric tyrosine kinase p210. 3 Because of fusion of the autoinhibitory SH3 domain of c-Abl to Bcr, autoinhibition of Abl kinase by its SH3 domain is disrupted. As a result, the chimeric kinase is constitutively activated. [4][5][6] Constitutively active p210 kinase appears to play a fundamental role as the primary causative factor in CML. The presence of this kinase is essential and sufficient for malignant transformation of hematopoietic cells in culture, 7,8 and expression of p210 in transgenic mice causes a CML-like myeloproliferative disease. 9,10 Treatment of Bcr-Abl-transformed hematopoietic cells with potent inhibitors of the p210 kinase, such as Gleevec (also known as imatinib mesylate or STI-571) [11][12][13]14 leads to growth inhibition and apoptosis. The therapeutic efficacy of imatinib mesylate has been demonstrated in patients with CML. 12,13 Although biological effects mediated by Bcr-Abl tyrosine kinase have been extensively characterized, the molecular mechanisms by which the oncogenic kinase transforms hematopoietic cells are not fully understood. Bcr-Abl kinase induces hematopoietic cell transformation by a...

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“…Murine hematopoiesis arises in yolk sac blood islands and becomes morphologically identifiable at E7.0 to 7.5. 31,32 At first, primitive erythroid progenitors comprise nearly all blood island progenitors; however, definitive progenitors begin to emerge at E8.25. 33 We have investigated the temporal emergence of Tpo and c-mpl mRNA transcripts and examined the biologic responsiveness of early yolk sac and embryo proper hematopoietic progenitors to pharmacologic doses of Tpo in vitro.…”

Section: Discussionmentioning

confidence: 99%