Role of cytokines in the treatment of acute leukemias: a review

Ravandi, Farhad

doi:10.1038/sj.leu.2404152

Cited by 33 publications

(27 citation statements)

References 82 publications

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“…In addition, GM-CSF and IL-5 were important in normal response to certain infections [4,14,24]. However, it is the established clinical utility of GM-CSF, and more recently G-CSF, which are used to treat significant granulocytopaenia, for example following chemotherapy [25], that underpins the importance of these signalling pathways.…”

Section: Introductionmentioning

confidence: 99%

Crossing paths: interactions between the cell death machinery and growth factor survival signals

Brumatti

Salmanidis

Ekert

2010

Cell. Mol. Life Sci.

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Cytokines and growth factors play a crucial role in the maintenance of haematopoietic homeostasis. They transduce signals that regulate the competing commitments of haematopoietic stem cells, quiescence or proliferation, retention of stem cell pluripotency or differentiation, and survival or demise. When the balance between these commitments and the requirements of the organisms is disturbed, particularly when it favours survival and proliferation, cancer may result. Cell death provoked by loss of growth factor signalling is regulated by the Bcl-2 family of apoptosis regulators, and thus survival messages transduced by growth factors must regulate the activity of these proteins. Many aspects of direct interactions between cytokine signalling and regulation of apoptosis remain elusive. In this review, we explore the mechanisms by which cytokines, in particular Interleukin-3 and granulocyte-macrophage colony-stimulating factor, promote cell survival and suppress apoptosis as models of how cytokine signalling and apoptotic pathways intersect.

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Section: Introductionmentioning

confidence: 99%

Crossing paths: interactions between the cell death machinery and growth factor survival signals

Brumatti

Salmanidis

Ekert

2010

Cell. Mol. Life Sci.

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“…[121][122][123][124][125] However, in larger trials assessing the therapeutic impact in terms of differentiation of leukemia cells in AML or MDS, hematopoietic cytokines have had limited success. 126 A niche for hematopoietic cytokines in differentiation therapy exists in the treatment of congenital neutropenia disorder. In this disease, several decades of progress have identified pertubations of the G-CSF receptor signaling as one of the underlying causes, and the administration of G-CSF to these patients has overcome a block of myeloid differentiation leading to a substantial prolongation of their survival.…”

Section: Cytokinesmentioning

confidence: 99%

Differentiation therapy of leukemia: 3 decades of development

Nowak

Stewart

Koeffler

2009

Blood

312

241

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IntroductionA characteristic abnormality of leukemia cells is that they are blocked at an early stage of their development and fail to differentiate into functional mature cells. During the 1970s and 1980s, several scientific achievements popularized the strategy of inducing malignant cells to overcome their block of differentiation and enter the apoptotic pathways as an elegant alternative to killing cancer cells by cytotoxic therapies. This intervention could theoretically limit exposure to unwanted side effects of cytotoxic chemotherapy, and more importantly, improve complete remission and cure rates. Pioneering reports included studies demonstrating the differentiating capability of dimethylsulfoxide (DMSO) on erythropoiesis, 1 efforts to elucidate substances to control the differentiation of myeloid leukemia, 2 and the first evidence of the differentiating properties of retinoic acid. 3,4 The initial promising preclinical results of this approach prompted a review article by us 25 years ago concerning the possibilities and therapeutic implications of differentiation induction in leukemia. 5 At that stage, cell line models for in vitro differentiation experiments were described. Substances such as phorbol diesters, teleocidins, polar planar drugs, cytokines, retinoids, and vitamin D metabolites showed dramatic potential to differentiate cell lines such as HL-60, KG-1, ML-3, or K562 in vitro and fueled the hope of developing a new approach to treat cancers by overcoming their blocked differentiation. Today, 25 years later, we discuss the progress and the clinical achievements of this therapeutic approach. Ligands of nuclear hormone receptorsPoster child of success: complete remissions of APL by differentiation therapyThe potential for differentiating therapy to improve cure rates in leukemia is exemplified by the development of all-trans retinoic acid (ATRA) for the targeted treatment of acute promyelocytic leukemia (APL). One of the most remarkable results of initial in vitro experiments was achieved in differentiating HL-60 cells with ATRA, which produced terminal differentiation in 90% of cells with 10 Ϫ6 M retinoic acid. 3 Investigators soon realized that ATRA was specifically effective in APL cells carrying a typical chromosomal translocation between chromosomes 15 and 17 [t(15;17)(q22; q21)] 6 but not in other leukemias. 4 The first APL patients treated with ATRA in the early 1980s achieved encouraging remissions by the new therapy. [7][8][9][10] The first clinical trial of ATRA reported 16 newly diagnosed, and 8 anthracycline refractory patients who were induced with single-agent ATRA. Complete hematologic remission was induced in all patients; more than 90% of samples from these individuals demonstrated in vitro evidence of blast differentiation. 10 This seminal trial changed the management and prognosis of APL, and introduced a paradigm for success of cell differentiation therapy. Subsequently, APL therapy was improved stepwise through elucidation of the most effective combination regimen of ATRA wit...

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“…The role of cytokines in the treatment of acute leukemias including AML has been investigated in several studies because of their immunologic and/or cycling properties (21). Cytokines such as IL-2, granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-CSF (GM-CSF) have been mainly used as adjuvants of chemotherapy, as they may stimulate immune cells (22) or limit the duration of neutropenia and promote cell cycling of quiescent leukemia cells, making them more sensitive to chemotherapeutic drugs (21).…”

Section: Introductionmentioning

confidence: 99%

Interleukin-27 Inhibits the Growth of Pediatric Acute Myeloid Leukemia in NOD/SCID/Il2rg−/− Mice

Zorzoli

Carlo

Cocco

et al. 2012

Clinical Cancer Research

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Purpose: Acute myeloid leukemia (AML) accounts for more than half of fatal cases in all pediatric leukemia patients; this observation highlights the need of more effective therapies. Thus, we investigated whether interleukin (IL)-27, an immunomodulatory cytokine, functions as an antitumor agent against pediatric AML cells.Experimental Design: Expression of WSX-1 and gp130 on AML cells from 16 pediatric patients was studied by flow cytometry. Modulation of leukemia cell proliferation or apoptosis upon IL-27 treatment in vitro was tested by bromodeoxyuridine/propidium iodide (PI) and Ki67, or Annexin V/PI staining and flow cytometric analysis. The angiogenic potential of AML cells treated or not with IL-27 was studied by chorioallantoic membrane assay and PCR array. In vivo studies were carried out using nonobese diabetic/ severe combined immunodeficient (NOD/SCID)/Il2rg À/À mice injected intravenously with five pediatric AML cell samples. Leukemic cells engrafted in PBS and IL-27-treated animals were studied by immunohistochemical/morphologic analysis and by PCR array for expression angiogenic/dissemination-related genes. Results: We provided the first demonstration that (i) AML cells injected into NOD/SCID/Il2rgÀ/À mice gave rise to leukemia dissemination that was severely hampered by IL-27, (ii) compared with controls, leukemia cells harvested from IL-27-treated mice showed significant reduction of their angiogenic and spreading related genes, and (iii) similarly to what was observed in vivo, IL-27 reduced in vitro AML cell proliferation and modulated the expression of different genes involved in the angiogenic/spreading process. Conclusion: These results provide an experimental rationale for the development of future clinical trials aimed at evaluating the toxicity and efficacy of IL-27.

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Role of cytokines in the treatment of acute leukemias: a review

Cited by 33 publications

References 82 publications

Crossing paths: interactions between the cell death machinery and growth factor survival signals

Crossing paths: interactions between the cell death machinery and growth factor survival signals

Differentiation therapy of leukemia: 3 decades of development

Interleukin-27 Inhibits the Growth of Pediatric Acute Myeloid Leukemia in NOD/SCID/Il2rg−/− Mice

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