Jak2 inhibition deactivates Lyn kinase through the SET–PP2A–SHP1 pathway, causing apoptosis in drug-resistant cells from chronic myelogenous leukemia patients

Samanta, Abhishek; Chakraborty, Sharmistha; Wang, Y; Kantarjian, Hagop M.; Sun, Xiaoping; Hood, John; Perrotti, Danilo; Arlinghaus, Ralph B.

doi:10.1038/onc.2009.7

Cited by 109 publications

(124 citation statements)

References 34 publications

(61 reference statements)

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“…In BCR-ABL1 + myeloid progenitors, JAK2 interacts with BCR-ABL1 and upregulates SET leading to PP2A inactivation (27), while forced PP2A reactivation results in JAK2 inhibition (15). Because BCR-ABL1 activity in CD34 + CD38 -cells is reduced by JAK2 inhibition, and JAK2 inhibited PP2A and was associated with and equally induced by WT and kinase-deficient K1172R BCR-ABL1 in primary mouse LSK and 32Dcl3 myeloid cells (Figure 4, A and B, and Supplemental Figure 2), it is possible that BCR-ABL1 recruits JAK2 and allows its activation (48), and OSU-2S (49) are also shown.…”

Section: Survival and Self-renewal Of Quiescent CML Hscs Requires Silmentioning

confidence: 99%

PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells

et al. 2013

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Section: Survival and Self-renewal Of Quiescent CML Hscs Requires Silmentioning

confidence: 99%

PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells

et al. 2013

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“…9,10 On the other hand, JAK2 constitutive activity 49,50 and SETBP1 overexpression in BCR/ABL-negative AML 37 might independently contribute to PP2A inactivation. Our results show that the mechanisms of PP2A inactivation in AML might be the overexpression of the physiological PP2A inhibitors CIP2A 33 and SET, 51 the overexpression of SETBP1, or the downregulation of PP2A subunits, suggesting that dysfunction of several distinct PP2A complexes may contribute to cell transformation.…”

Section: Pp2a Inhibition In Aml I Cristóbal Et Almentioning

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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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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“…In human chronic myeloid leukemia, Jak2, downstream target of Bcr-Abl, increases SET protein level [22]. Jak2 inhibition or knockdown reduces SET protein and increases PP2A activity.…”

Section: Discussionmentioning

confidence: 99%

A Potential Therapeutic Application of SET/I2PP2A Inhibitor OP449 for Canine T-cell Lymphoma

Fujiwara

Kawasaki

Yabe

et al. 2013

The Journal of Veterinary Medical Science

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ABSTRACT. Lymphoma is one of the most common malignant tumors in canine. Chemotherapy results in a high rate of remission; however, relapse and clinical drug resistance are usually seen within a year. Protein phosphatase 2A (PP2A) acts as a tumor suppressor and plays a critical role in mammalian cell transformation. Increased protein levels of SET, endogenous PP2A inhibitor, have been reported to correlate with poor prognosis in human leukemia. Here, we test the potential therapeutic role for a SET antagonist in canine lymphoma. We observed SET protein levels increased in multiple canine lymphoma cell lines compared with primary peripheral blood cells. A novel SET antagonist OP449 increased PP2A activity and effectively killed SET high-expressing canine lymphoma cells, but not SET low-expressing cells. Caspase-3 activation and enhanced Annexin V positive staining were observed after OP449 treatment, suggesting apoptotic cell death by OP449. Consistent with this, pan-caspase inhibitor Z-VAD-FMK blocked OP449 induced cell death. These data demonstrated the potential therapeutic application of SET antagonists for canine lymphoma. KEY WORDS: apoptosis, canine lymphoma, OP449, protein phosphatase 2A, SET.

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Jak2 inhibition deactivates Lyn kinase through the SET–PP2A–SHP1 pathway, causing apoptosis in drug-resistant cells from chronic myelogenous leukemia patients

Cited by 109 publications

References 34 publications

PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells

PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells

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

A Potential Therapeutic Application of SET/I2PP2A Inhibitor OP449 for Canine T-cell Lymphoma

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