Effect of transcription-factor concentrations on leukemic stem cells

Rosenbauer, Frank; Koschmieder, Steffen; Steidl, Ulrich; Tenen, Daniel G.

doi:10.1182/blood-2005-02-0717

Cited by 88 publications

(70 citation statements)

References 75 publications

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Section: Launchingmentioning

confidence: 99%

“…Knock-in mice expressing an amino terminal truncated 30 kd isoform (p30) lacking TAD1 develop myeloid leukemia, again in contrast to the non-malignant phenotype of their null counterparts [30]. Nevertheless, C/EBPα−/− mice do display an expanded HSC compartment reminiscent of that seen in AML1-ETO transduced progenitors [30]. In a series of 137 patients with AML, 10 samples (∼7%) displayed heterozygous coding mutations which in 5 cases led to the expression of the p30 dominant negative isoform [41].…”

Section: Launchingmentioning

confidence: 99%

“…While both studies do not categorically rule out a role for RUNX1 target gene repression by copreressor recruitment, they emphasize that AML1-ETO leukemogenesis clearly depends on alternative pathways in primary cell systems. [30]. In particular, lineage commitment defects induce expansion of a self-renewing progenitor compartment, which may then be poised for leukemic transformation through additional mutations.…”

Section: Challenges To the Classical Model: Gene Expression Profilesmentioning

confidence: 99%

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Oncogenic pathways of AML1-ETO in acute myeloid leukemia: Multifaceted manipulation of marrow maturation

Elagib¹,

Goldfarb²

2007

Cancer Letters

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The leukemic fusion protein AML1-ETO occurs frequently in human acute myeloid leukemia (AML) and has received much attention over the past decade. An initial model for its pathogenetic effects emphasized the conversion of a hematopoietic transcriptional activator, RUNX1 (or AML1), into a leukemogenic repressor which blocked myeloid differentiation at the level of target gene regulation. This view has been absorbed into a larger picture of AML1-ETO pathogenesis, encompassing dysregulation of hematopoietic stem cell homeostasis at several mechanistic levels. Recent reports have highlighted a multifaceted capacity of AML1-ETO directly to inhibit key hematopoietic transcription factors that function as tumor suppressors at several nodal points during hematopoietic differentiation. A new model is presented in which AML1-ETO coordinates expansion of the stem cell compartment with diminished lineage commitment and with genome instability.

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Section: Launchingmentioning

confidence: 99%

Section: Launchingmentioning

confidence: 99%

Section: Challenges To the Classical Model: Gene Expression Profilesmentioning

confidence: 99%

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Oncogenic pathways of AML1-ETO in acute myeloid leukemia: Multifaceted manipulation of marrow maturation

Elagib¹,

Goldfarb²

2007

Cancer Letters

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“…A small group of transcription factors, such as CCAAT/enhancer-binding protein a (C/EBPa), Runx1 (originally named acute myeloid leukemia 1 (AML1)) and PU.1, play crucial roles in controlling normal hematopoiesis (Friedman, 2002). The structural and functional abnormalities of these factors also contribute to the pathogenesis of AML, in which the normal differentiation program is blocked (Peterson and Zhang, 2004;Rosenbauer et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-inducible factor-1α-induced differentiation of myeloid leukemic cells is its transcriptional activity independent

Wang

Zhang

et al. 2007

Oncogene

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Hypoxia or hypoxia mimetic has been shown to induce differentiation together with the accumulation of hypoxiainducible factor-1a (HIF-1a) protein of myeloid leukemic cells and normal hematopoietic progenitors. To provide direct evidence for the role of HIF-1a in acute myeloid leukemia (AML) cell differentiation and its mechanisms, we generated myeloid leukemic U937T transformants, in which HIF-1a was tightly induced by tetracycline withdrawal. The results showed that the conditional HIF-1a induction triggered granulocytic differentiation of these transformants, while the suppression of HIF-1a expression by specific short hairpin RNAs (shRNAs) effectively inhibited hypoxia-induced differentiation of U937 cells, as evidenced by morphology, maturation-related antigens as well as expressions of myeloid differentiation signatures and hematopoietic cells-specific cytokine receptors. The specific shRNAs-inhibited expression of HIF-1b, an essential partner for transcription activity of HIF-1, failed, while the inhibition of hematopoietic differentiation-critical CCAAT/enhancer-binding protein-a (C/EBPa) significantly eliminated HIF-1a-mediated myeloid leukemic cell differentiation. Collectively, this work provided several lines of direct evidence for the role of HIF-1a protein through its nontranscriptional activity in myeloid cell differentiation, in which C/EBPa elicits a role as an effector downstream to HIF-1a. These discoveries would shed new insights for understanding mechanisms underlying leukemogenesis and designing the new therapeutic strategy for differentiation induction of AML.

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“…Reduction of Pu.1 activity below 20% of normal one lead to poor differentiation of an abnormal progenitor pool is reminiscent of a preleukemic phase. Additional secondary mutation, such as c-myc overexpression, complete the transformation of those cells into Leukemic stem cells (Rosenbauer et al, 2005). Knockdown of the transcription factor PU.1 gene leads to AML in mice.…”

Section: Pu1 and Leukemic Stem Cellsmentioning

confidence: 99%

Cancer stem cells in leukemia, recent advances

Zou

2007

Journal Cellular Physiology

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The history of stem cell research was started in the early 1900s in Europe where the researcher realized that various types of blood cells came from a particular ''stem cells.'' However, it was not until 1963 that the first quantitative description of the self-renewal activities of transplanted mouse bone marrow cells were documented by Canadian scientist Ernest A McCulloch and James E Till in Toronto. The concept of cancer stem cells has been used over 50 years ago; whereas the strong evidence for the existence of a Cancer Stem Cells was obtained recently. Consequently, there is increasing attention in recent year about cancer stem cells. The findings from recent studies support the concept that stem cells are integral to the development of several forms of human cancer. Changes in stem cell behavior can contribute to tumor formation. Leukemia is a cancer of blood-forming tissue, including the bone marrow and lymphatic system. Leukemic stem cells represent the cancer stem cells in the leukemia. In this review, we summarize the recent advance in the study of leukemic stem cells.J (Soltysova et al., 2005). It has been suggested that probably both mechanisms are involved in the origin of cancer stem cells (see Fig. 1). Dysregulation of normal stem cell self-renewal is a possible requirement for the development of cancer. Recently, isolation and characterization of cancer stem cells in human tumors and in tumor cell lines has been successful. The existence of cancer stem cells has been proven in acute and chronic myeloid leukemia, breast cancer, brain tumors, lung cancer and in gastrointestinal tumors, such as pancreatic cancer (Li et al., 2007). Cancer stem cell model also has implication in clinical oncology: although standard chemotherapy kills most cells in a tumor, cancer stem cells remain drug resistant and viable. The small number of cancer stem cells might cause tumor recurrence. Tumor metastases and growth in distinct areas of body and their cellular heterogeneity has been suggested to be the result of cancer stem cell differentiation and/or dedifferentiation. Further characterization of cancer stem cells is necessary in order to find ways to destroy them, which might contribute significantly to the therapeutic strategy of cancer. Normal Hematopoiesis and RegulationHematopoietic stem cells (HSCs) were first identified by two Canadian scientists Till and McCulloch in murine bone marrow cells in 1961 (Till and McCulloch, 1961). Blood cells are continuingly produced throughout our life time from rare pluirpotent bone marrow stem cells. In embryo stage, the hematopoietic system is a derivative of mesoderm, and embryonic hematopoiesis emerges in the blood islands of the yolk sac. Adult hematopoiesis is transient in fetal liver but later sustained mainly in the bone marrow. In human, HSCs are highly enriched in the fraction of CD34 þ bone marrow cells. Mouse HSCs express very low level of CD34 antigen on their surface, whereas the c-kit þ Sca-1 þ bone marrow cells are more representative for mouse HSCs. A speci...

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Effect of transcription-factor concentrations on leukemic stem cells

Cited by 88 publications

References 75 publications

Oncogenic pathways of AML1-ETO in acute myeloid leukemia: Multifaceted manipulation of marrow maturation

Oncogenic pathways of AML1-ETO in acute myeloid leukemia: Multifaceted manipulation of marrow maturation

Hypoxia-inducible factor-1α-induced differentiation of myeloid leukemic cells is its transcriptional activity independent

Cancer stem cells in leukemia, recent advances

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