Gatekeeper pathways and cellular background in the pathogenesis and therapy of AML

Cammenga, Jörg

doi:10.1038/sj.leu.2403894

Cited by 17 publications

(8 citation statements)

References 94 publications

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“…It has been demonstrated that DC are not activated in human cancers and that their function is compromised by the tumor (1)(2)(3)(4)(5)(6). Several lines of evidence indicate that the ability of tumors to affect DC maturation and differentiation may result in a generalized failure of the host to mount an effective antitumor response.…”

Section: Endritic Cells (Dc)mentioning

confidence: 99%

Tumor Exosomes Inhibit Differentiation of Bone Marrow Dendritic Cells

Liu

et al. 2007

The Journal of Immunology

375

303

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The production of exosomes by tumor cells has been implicated in tumor-associated immune suppression. In this study, we show that, in mice, exosomes produced by TS/A murine mammary tumor cells target CD11b+ myeloid precursors in the bone marrow (BM) in vivo, and that this is associated with an accumulation of myeloid precursors in the spleen. Moreover, we demonstrate that TS/A exosomes block the differentiation of murine myeloid precursor cells into dendritic cells (DC) in vitro. Addition of tumor exosomes at day 0 led to a significant block of differentiation into DC, whereas addition at later time points was less effective. Similarly, exosomes produced by human breast tumor cells inhibited the differentiation of human monocytes in vitro. The levels of IL-6 and phosphorylated Stat3 were elevated 12 h after the tumor exosome stimulation of murine myeloid precursors, and tumor exosomes were less effective in inhibiting differentiation of BM cells isolated from IL-6 knockout mice. Addition of a rIL-6 to the IL-6 knockout BM cell culture restored the tumor exosome-mediated inhibition of DC differentiation. These data suggest that tumor exosome-mediated induction of IL-6 plays a role in blocking BM DC differentiation.

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Section: Endritic Cells (Dc)mentioning

confidence: 99%

Tumor Exosomes Inhibit Differentiation of Bone Marrow Dendritic Cells

Liu

et al. 2007

The Journal of Immunology

375

303

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“…Changes in transcriptional control of hematopoietic cells and mutations involving different proto-oncogenes or tumor suppressors account for the deregulation of normal myelopoiesis (3). Such changes ultimately result in activation of cellular pathways that mediate signals that promote cell growth and/or maintain survival, leading to leukemogenesis (4, 5). …”

Section: Introductionmentioning

confidence: 99%

Dual mTORC2/mTORC1 Targeting Results in Potent Suppressive Effects on Acute Myeloid Leukemia (AML) Progenitors

Altman

Sassano

Kaur

et al. 2011

Clinical Cancer Research

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Purpose To determine whether mTORC2 and RI-mTORC1 complexes are present in AML cells and to examine the effects of dual mTORC2/mTORC1 inhibition on primitive AML leukemic progenitors. Experimental Design Combinations of different experimental approaches were used, including immunoblotting to detect phosphorylated/activated forms of elements of the mTOR pathway in leukemic cell lines and primary AML blasts; cell proliferation assays; direct assessment of mRNA translation in polysomal fractions of leukemic cells; and clonogenic assays in methylcellulose to evaluate leukemic progenitor colony formation. Results mTORC2 complexes are active in AML cells and play critical roles in leukemogenesis. Rapamycin insensitive (RI) mTORC1 complexes are also formed and regulate the activity of the translational repressor 4E-BP1 in AML cells. OSI-027, blocks mTORC1 and mTORC2 activities and suppresses mRNA translation of cyclin D1 and other genes that mediate proliferative responses in AML cells. Moreover, OSI-027 acts as a potent suppressor of primitive leukemic precursors from AML patients and is much more effective than rapamycin in eliciting antileukemic effects in vitro. Conclusions Dual targeting of mTORC2 and mTORC1 results in potent suppressive effects on primitive leukemic progenitors from AML patients. Inhibition of the mTOR catalytic site with OSI-027 results in suppression of both mTORC2 and RI-mTORC1 complexes and elicits much more potent antileukemic responses than selective mTORC1 targeting with rapamycin.

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“…Indeed, changes in the transcriptional control in hematopoietic cells modify the arrays of signal transduction effectors available for growth factor receptors, whereas activating mutations in signal transduction molecules induce alterations in the activity and expression of several transcription factors that are essential for normal myeloid differentiation. 13,14 The phosphoinositide 3-kinase (PI3K)/Akt signaling network is crucial to widely divergent physiological processes that include cell cycle progression, differentiation, transcription, translation and apoptosis. 15,16 It is targeted by genomic aberrations including amplification, mutation and rearrangement more frequently than any other pathway in human cancer, with the possible exception of the p53 and retinoblastoma pathways.…”

Section: Introductionmentioning

confidence: 99%