FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome–positive acute lymphocytic leukemia

Neviani, Paolo; Santhanam, Ramasamy; Oaks, Joshua J.; Eiring, Anna M.; Notari, Mario; Blaser, Bradley W.; Liu, Shujun; Trotta, Rossana; Muthusamy, Natarajan; Gambacorti‐Passerini, Carlo; Druker, Brian J.; Cortes, Jorge; Marcucci, Guido; Chen, Ching Shih; Verrills, Nicole M.; Roy, Denis; Caligiuri, Michael A.; Bloomfield, Clara D.; Byrd, John C.; Perrotti, Danilo

doi:10.1172/jci31095

Cited by 324 publications

(425 citation statements)

References 77 publications

(99 reference statements)

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“…It has been reported that impaired PP2A activity has a key role in BCR/ABL-positive leukemias, such as CML and acute lymphoblastic leukemia, 31,32 in myeloid precursors expressing imatinib-sensitive (V560G) and imatinib-resistant (D816 V) mutant c-KIT, 36 and also in chronic lymphocytic leukemia; 46 moreover, activation of PP2A by either FTY720 or forskolin seems to have promising therapeutic effects in these diseases. Abbreviation: AML, acute myeloid leukemia.…”

Section: Discussionmentioning

confidence: 99%

“…[24][25][26][27][28][29][30] With regard to the endogenous PP2A inhibitors, upregulation of SET by the BCR/ABL oncogene leads to the suppression of PP2A, and contributes to leukemogenesis in chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia. 31,32 In addition, Junttila et al 33 provide strong evidence that cancerous inhibitor of PP2A (CIP2A) selectively targets PP2A associated with c-Myc to inhibit its phosphatase activity and protect Ser62 from dephosphorylation. Interestingly, CIP2A expression is upregulated in transformed cell lines and cancer tissue samples.…”

Section: Introductionmentioning

confidence: 99%

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PP2A impaired activity is a common event in acute myeloid leukemia and its activation by forskolin has a potent anti-leukemic effect

et al. 2011

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Protein phosphatase 2A (PP2A) is a human tumor suppressor that inhibits cellular transformation by regulating the activity of several signaling proteins critical for malignant cell behavior. PP2A has been described as a potential therapeutic target in chronic myeloid leukemia, Philadelphia chromosome-positive acute lymphoblastic leukemia and B-cell chronic lymphocytic leukemia. Here, we show that PP2A inactivation is a recurrent event in acute myeloid leukemia (AML), and that restoration of PP2A phosphatase activity by treatment with forskolin in AML cells blocks proliferation, induces caspase-dependent apoptosis and affects AKT and ERK1/2 activity. Moreover, treatment with forskolin had an additive effect with Idarubicin and Ara-c, drugs used in standard induction therapy in AML patients. Analysis at protein level of the PP2A activation status in a series of patients with AML at diagnosis showed PP2A hyperphosphorylation in 78% of cases (29/37). In addition, we found that either deregulated expression of the endogenous PP2A inhibitors SET or CIP2A, overexpression of SETBP1, or downregulation of some PP2A subunits, might be contributing to PP2A inhibition in AML. In conclusion, our results show that PP2A inhibition is a common event in AML cells and that PP2A activators, such as forskolin or FTY720, could represent potential novel therapeutic targets in AML.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PP2A impaired activity is a common event in acute myeloid leukemia and its activation by forskolin has a potent anti-leukemic effect

et al. 2011

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“…An action that is independent of FTY720 phosphorylation was reported in chronic myelogenous leukaemia (CML) cells, in which the fusion protein BCR-ABL drives proliferation: here, FTY720 triggered the activation of the protein phosphatase PP2A and, consequently, apoptosis 129 . Interestingly, PP2A regulates PKCs and PKB/Akt, providing another crossover point with PI3K signalling.…”

Section: Therapeutic Opportunitiesmentioning

confidence: 96%

Lipid signalling in disease

Wymann

Schneiter

2008

Nat Rev Mol Cell Biol

1,126

906

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“…26 More recently, evidence has been found to suggest that targeting autophagy, a process that allows cells to adapt to environmental stresses, might also allow CML stem and progenitor cells to be effectively targeted. 127 Other potential strategies include induction of protein phosphatase-2A activation by FTY720 128,129 and exposure of CML stem cells to the farnesyltransferase inhibitor (BMS-214662). 25,130 In addition, we have been pursuing a potential strategy based on targeting JAK2 to inhibit the activity of a biologically important multi-molecular complex that we have recently shown it forms with AHI-1, a novel signalling intermediate encoded by the Abelson helper integration site 1 (AHI-1) gene and the BCR-ABL oncoprotein.…”

Section: Properties That Affect Responses To Bcr-abl-targeted Therapementioning

confidence: 99%

Insights into the stem cells of chronic myeloid leukemia

et al. 2010

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Chronic myeloid leukemia (CML) has long served as a paradigm for generating new insights into the cellular origin, pathogenesis and improved approaches to treating many types of human cancer. Early studies of the cellular phenotypes and genotypes represented in leukemic populations obtained from CML patients established the concept of an evolving clonal disorder originating in and initially sustained by a rare, multipotent, self-maintaining hematopoietic stem cell (HSC). More recent investigations continue to support this model, while also revealing new insights into the cellular and molecular mechanisms that explain how knowledge of CML stem cells and their early differentiating progeny can predict the differing and variable features of chronic phase and blast crisis. In particular, these emphasize the need for new agents that effectively and specifically target CML stem cells to produce non-toxic, but curative therapies that do not require lifelong treatments.

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FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome–positive acute lymphocytic leukemia

Cited by 324 publications

References 77 publications

PP2A impaired activity is a common event in acute myeloid leukemia and its activation by forskolin has a potent anti-leukemic effect

PP2A impaired activity is a common event in acute myeloid leukemia and its activation by forskolin has a potent anti-leukemic effect

Lipid signalling in disease

Insights into the stem cells of chronic myeloid leukemia

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