Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop

Oliveira, João Bosco; Bleesing, Jack J.; Dianzani, Umberto; Fleisher, Thomas A.; Jaffe, Elaine S.; Lenardo, Michael J.; Rieux-Laucat, Frédéric; Siegel, Richard M.; Su, Helen C.; Teachey, David T.; Rao, V. Koneti

doi:10.1182/blood-2010-04-280347

Cited by 438 publications

(457 citation statements)

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“…ALPS is diagnosed by a combination of clinical findings and laboratory abnormalities, including elevation of an atypical T-cell population in peripheral blood termed double negative T-cells (DNTs; cell phenotype CD3+, CD4−, CD8−, T-cell receptor [TCR] α/β+), biomarkers (elevated plasma IL-10, IL-18, vitamin B 12 , or soluble-FasL, as well as polyclonal hypergammaglobulinemia), mutations in ALPS causative genes (FAS, FASL, CASPIO), and in vitro evidence of defective Fas-mediated apoptosis. [216] Many patients with ALPS require treatment, most commonly because of autoimmune cytopenias. Some patients only require corticosteroid bursts with disease flares; however, other patients require daily treatment.…”

Section: Lymphoproliferative Disordersmentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

et al. 2012

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The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen.Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual-and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignanc...

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Section: Lymphoproliferative Disordersmentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

et al. 2012

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“…9,10 Approximately one-third of patients with ALPS have yet undetermined genetic defects (ALPS-U). 11 Treatment of patients with ALPS varies significantly, with no consensus on the management. We have previously demonstrated that treatment with the mammalian target of rapamycin inhibitor, sirolimus (Rapamune) led to a complete response (CR) in a small retrospective cohort of 5 children with corticosteroid refractory ALPS.…”

Section: Introductionmentioning

confidence: 99%

Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial

Bride

Vincent

Smith‐Whitley

et al. 2016

Blood

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“…Finally, potent small molecule inhibitors of kinase effectors of Ras-GTP have been developed as anticancer agents (see figure). In vitro studies performed by Oliveira and colleagues 10 provide intriguing evidence that drugs that target MEK, a downstream component of the Raf/MEK/ERK pathway, may reverse the cellular and biochemical defects seen in RALD. Similarly, inhibitors of PI3 kinase signaling, which plays a central role in lymphocyte survival and is frequently altered by somatic mutations in T-ALL, 13 are appealing as potential therapeutic agents.…”

Section: Oncogenic Ras Scales the Alps ------------------------------mentioning

confidence: 99%

“…Niemela et al found that patient T cells that were deprived of IL-2 failed to induce the proapoptotic protein BIM, 1 which was also true in the previous case with an NRAS mutation. 10 Together, the clinical and biologic features of LPD in individuals with KRAS and NRAS mutations establish this disorder as a distinct entity of Ras-associated lymphoproliferative disease (RALD). 10 The pathogenesis of RALD likely involves the dominant clonal outgrowth of progeny of a primitive hematopoietic cell that sustains a RAS gene mutation.…”

Section: Oncogenic Ras Scales the Alps ------------------------------mentioning

confidence: 99%

“…10 Affected individuals show increased numbers of "double-negative" T (DNT) cells, which lack CD4 and CD8 expression and show defective Fas-mediated apoptosis. By contrast, the DNT population is not increased in patients with KRAS or NRAS mutations, and Fas pathway activation provokes a normal apoptotic response.…”

Section: Oncogenic Ras Scales the Alps ------------------------------mentioning

confidence: 99%

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Oncogenic Ras scales the ALPS

Shannon

2011

Blood

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Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop

Cited by 438 publications

References 35 publications

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial

Oncogenic Ras scales the ALPS

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