A comparison of normal and leukemic stem cell biology in Chronic Myeloid Leukemia

Jørgensen, Heather G.; Holyoake, Tessa L.

doi:10.1002/hon.667

Cited by 17 publications

(9 citation statements)

References 85 publications

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“…More is known about the molecular cell biology of this oncogene than any other associated with leukemia. The ABL (c-abl oncogene 1) proto-oncoprotein exists in the nucleus, bound to chromatin, and in the cytoplasm, co-localized with F-actin [57]. BCR/ABL is found in the cytoplasm predominantly.…”

Section: Bcr/ablmentioning

confidence: 99%

The Use of Proteomics for Systematic Analysis of Normal and Transformed Hematopoietic Stem Cells

Cadeco

Williamson²,

Whetton³

2012

CPD

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Blood cell production involves the commitment and differentiation of hematopoietic stem cells to committed progenitor cells which undergo a programmed development to form mature cells such as neutrophils, macrophages and lymphocytes. This complex process can be disrupted in diseases such as the leukemias and myeloproliferative disorders by oncogenes such as protein tyrosine kinases. The analysis of expression patterns for specific genes suggests that the regulation of protein expression can be achieved in a posttranslational fashion. Post-translational protein modification, such as phosphorylation and acetylation govern events in blood cell production and yet cannot be measured using conventional molecular biology approaches. For this reason a suite of techniques in mass spectrometry needs to be applied to define regulation and disregulation in normal and abnormal hematopoiesis. These approaches include discovery proteomics with relative quantification of thousands of proteins. Alternatively targeted examination of a single protein to identify its interaction partners or post-translational modifications using mass spectrometry reveals much mechanistic detail. The use of mass spectrometry and proteomics approaches in stem cell and leukemia studies has thus far revealed a good deal of information on hematopoiesis. Further application of the proteomics approach is a necessity to gain true insight into regulatory processes governing the production of billions of blood cells a day, and ways in which that process can be manipulated to therapeutic advantage.

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Section: Bcr/ablmentioning

confidence: 99%

The Use of Proteomics for Systematic Analysis of Normal and Transformed Hematopoietic Stem Cells

Cadeco

Williamson²,

Whetton³

2012

CPD

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“…The majority of normal HSCs are a quiescent cell population stabilized in the G 0 stage of the cell cycle, with each cell cycling every 1-3 months. 122,123 It has been shown that CML develops as a consequence of characteristic changes within the HSCs. Almost all neoplastic clones carry the cytogenetic abnormality, Ph, and the fusion oncogene, Bcr-Abl.…”

Section: "Quiescent" CML Stem Cellsmentioning

confidence: 99%

The Bcr-Abl tyrosine kinase inhibitor imatinib and promising new agents against Philadelphia chromosome-positive leukemias

2007

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Chronic myeloid leukemia (CML) was the first human malignant disease to be linked to a single, acquired genetic abnormality. Identification of the Bcr-Abl kinase fusion protein and its pivotal role in the pathogenesis of CML provided new opportunities to develop molecular-targeted therapies. Imatinib mesylate (IM, Gleevec, Novartis Pharmaceuticals, Basel, Switzerland), which specifically inhibits the autophosphorylation of the Abl TK, has improved the treatment of CML. However, resistance is often reported in patients with advanced-stage disease. Several novel TK inhibitors have been developed that override IM resistance mechanisms caused by point mutations within the Abl kinase domain. Inhibitors of Abl TK are divided into two main groups, namely, ATP-competitive and ATP noncompetitive inhibitors. The ATP-competitive inhibitors fall into two subclasses, the Src/Abl inhibitors, and the 2-phenylaminopyrimidine-based compounds. Dasatinib (formerly BMS-354825), AP23464, SKI-606, and PD166326 are classified as Src/Abl inhibitors, while nilotinib (AMN107) and INNO-406 (NS-187) belong to the latter subclass of inhibitors. Of these agents, dasatinib and nilotinib underwent clinical trials earlier than the others and favorable results are now accumulating. Clinical studies of the other compounds, including SKI-606 and INNO-406, have been performed in rapid succession. Because of their strong affinities for the ATP-binding site compared to IM, most ATP-competitive inhibitors may be effective in IM-resistant patients. However, an ATP-competitive inhibitor that can inhibit the phosphorylation of T315I Bcr-Abl has not yet been developed. Instead, ATP noncompetitive inhibitors, such as ON012380, Aurora kinase inhibitor MK0457 (VX-680), and p38 MAP kinase inhibitor BIRB-796, have been developed to address this problem. This review provides an update on the underlying pathophysiologies of disease progression and IM resistance, and discusses the development of new targeted TK inhibitors for managing CML and the importance of future strategies targeting CML stem cells.

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“…Our experiments do not, however, address the mechanism whereby CML cells survive and proliferate when deprived of growth factor. This property is inevitably linked to the BCR/ABL oncogene, 10,15,29 and several molecular mechanisms have been proposed to explain the growth and survival of CML cells in low growth factor concentrations. 15,24,[29][30][31][32] Nevertheless, the in vivo action of increased elastase within the bone marrow of CML patients may explain several features of CML pathophysiology:…”

Section: Discussionmentioning

confidence: 99%

Clonal dominance of chronic myelogenous leukemia is associated with diminished sensitivity to the antiproliferative effects of neutrophil elastase

Ouriaghli

Sloand

Mainwaring

et al. 2003

Blood

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Clinical observations suggest that in chronic myelogenous leukemia (CML), the Philadelphia chromosome (Ph+) clone has a growth advantage over normal hematopoiesis. Patients with CML have high levels of neutrophil elastase, which has recently been shown to antagonize the action of granulocyte-colony-stimulating factor (G-CSF) and other growth factors. We therefore compared the effect of elastase on the growth of normal and CML progenitor cells. In 10-day suspension cultures of normal or CML CD34+ cells supplemented with G-CSF, stem cell factor (SCF), and granulocyte macrophage-colony-stimulating factor (GM-CSF), CML cells had diminished sensitivity to the growth inhibitory effect of elastase. When equal numbers of CML and normal CD34+ cells were cocultured for 10 days, there was no change in the relative proportions of normal and leukemic cells (measured by fluorescence in situ hybridization [FISH] or flow cytometry). However, when elastase was added, CML cells predominated at the end of the culture period (78% vs 22% with 1 microg/mL and 80% vs 20% with 5 microg/mL elastase). CML neutrophils substituted effectively for elastase in suppressing the proliferation of normal CD34+ cells, but this effect was abrogated by serine protease inhibitors. These results suggest that elastase overproduction by the leukemic clone can change the growth environment by digesting growth factors, thereby giving advantage to Ph+ hematopoiesis.

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A comparison of normal and leukemic stem cell biology in Chronic Myeloid Leukemia

Cited by 17 publications

References 85 publications

The Use of Proteomics for Systematic Analysis of Normal and Transformed Hematopoietic Stem Cells

The Use of Proteomics for Systematic Analysis of Normal and Transformed Hematopoietic Stem Cells

The Bcr-Abl tyrosine kinase inhibitor imatinib and promising new agents against Philadelphia chromosome-positive leukemias

Clonal dominance of chronic myelogenous leukemia is associated with diminished sensitivity to the antiproliferative effects of neutrophil elastase

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