Pim1 kinase synergizes with c-MYC to induce advanced prostate carcinoma

Prospective identification of patients whose chronic myeloid leukemia (CML) will progress to blast crisis is currently not possible. PP2A is a phosphatase and tumor suppressor that regulates cell proliferation, differentiation, and survival. Cancerous inhibitor of PP2A (CIP2A) is a recently described inhibitor of PP2A in breast and gastric cancer. The aim of this study was to investigate whether CIP2A played a role in CML and whether PP2A or its inhibitor proteins CIP2A or SET could predict clinical outcome. At the time of diagnosis of CML, patients who will later progress to blast crisis have significantly higher levels of CIP2A protein (P < .0001) than patients who do not progress, suggesting that PP2A is functionally inactive. We show that the potential mechanism for disease progression is via altered phosphorylation of the oncogene c-Myc. Knockdown of CIP2A results in increased PP2A activity, decreased c-Myc levels, and a decrease in BCR-ABL1 tyrosine kinase activity. We demonstrate that CIP2A levels at diagnosis can consistently predict patients who will progress to blast crisis. The data show that CIP2A is biologically and clinically important in CML and may be a novel therapeutic target. (Blood. 2011;117(24):6660-6668) IntroductionChronic myeloid leukemia (CML) is a malignant disease of the primitive hematologic cell, characterized by inappropriate expansion of myeloid cells. Although this disease is readily controlled by imatinib, approximately one-third of patients will eventually fail treatment 1,2 ; and a significant proportion of these will progress toward blast crisis (BC), which is usually rapidly fatal. Poor response to imatinib and progression to BC have been linked to high BCR-ABL1 tyrosine kinase activity, 3 but why one patient can remain in well-controlled chronic phase for decades whereas another may rapidly progress to BC is poorly understood.The BCR-ABL1 tyrosine kinase in CML is responsible for growth and survival of the malignant cells through activation of signaling pathways, such as the mitogen-activated protein kinase cascade and the PI3K pathway. 4,5 A major cellular serine/threonine phosphatase working to down-regulate activation of these pathways is the tumor suppressor protein phosphatase 2A (PP2A). 6 In CML cells, PP2A is a key target of BCR-ABL1 signaling; this protein becomes inactivated in these cells because BCR-ABL1 stimulates prevention of its auto-dephosphorylation at tyrosine 307 . 7,8 Maintenance of pY 307 -PP2A levels in CML cells feeds back to BCR-ABL1 and facilitates increased and sustained kinase activity. Inhibition of BCR-ABL1 by imatinib results in reactivation of PP2A, inducing both suppression of growth and enhanced apoptosis of the leukemic cells. 8 However, it is unknown whether Y 307 in PP2A is a direct substrate of BCR-ABL1, and the mechanism regulating phosphorylation of PP2A at this site is not clearly defined.One proposal for the mechanism through which BCR-ABL1 regulates PP2A activity in CML cells involves expression of the PP2A inhibitor protein SET. In ...

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“…ELISA methodology was adapted from Hamilton et al 22 using anti-Myc ser62 antibody 23 (Abcam) and anti-Myc antibody (New England Biolabs).…”

Section: C-myc Protein and Phosphorylation Statusmentioning

confidence: 99%

“…23 PIM1 is itself phosphorylated, and in this state it is active and its expression is stable. 25 However, this protein is a target for PP2A; and once it is dephosphorylated by PP2A, it is rapidly degraded in the proteasome.…”

Section: C-myc Protein Is Elevated At Diagnosis In Patients Destined mentioning

confidence: 99%

Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid leukemia is a critical determinant of disease progression

Lucas

Harris

Giannoudis

et al. 2011

Blood

120

121

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“…Although its cellular localization may be nuclear and/or cytoplasmic, nuclear localization is believed to be necessary for its biologic effects (9). In humans, PIM1 and c-MYC appear to have a cooperative role in prostate cancer (34), and increased expression of PIM1 has been noted in gastrointestinal cancers (35), pancreatic adenocarcinoma (36), and oral squamous-cell carcinoma (37). PIM1 also has been noted to be overexpressed in myeloid and lymphoid leukemias (32) and has been associated with B-cell lymphomas (4,9).…”

Section: Discussionmentioning

confidence: 99%

PIM1 gene cooperates with human BCL6 gene to promote the development of lymphomas

Baron¹,

Anastasi²,

Hyjek³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Diffuse large B-cell lymphomas in humans are associated with chromosomal rearrangements (∼40%) and/or mutations disrupting autoregulation (∼16%) involving the BCL6 gene. Studies of lymphoma development in humans and mouse models have indicated that lymphomagenesis evolves through the accumulation of multiple genetic alterations. Based on our prior studies, which indicated that carcinogen-induced DNA mutations enhance the incidence of lymphomas in our mouse model expressing a human BCL6 transgene, we hypothesized that mutated genes are likely to play an important cooperative role in BCL6 -associated lymphoma development. We used retroviral insertional mutagenesis in an effort to identify which genes cooperate with BCL6 in lymphomagenesis in our BCL6 transgenic mice. We identified PIM1 as the most frequently recurring cooperating gene in our murine BCL6-associated lymphomas (T- and B-cell types), and we observed elevated levels of PIM1 mRNA and protein expression in these neoplasms. Further, immunohistochemical staining, which was performed in 20 randomly selected BCL6-positive human B- and T-cell lymphomas, revealed concurrent expression of BCL6 and PIM1 in these neoplasms. As PIM1 encodes a serine/threonine kinase, PIM1 kinase inhibition may be a promising therapy for BCL6/PIM1-positive human lymphomas.

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“…(3)double mutant P53 (N340Q/ L344R) enhances HOTAIR expression and stimulates telomerase activity dependent on pim1. Pim-1 is associated with transcriptional activation [39]. Our previous studies showed that H19 enhanced Pim1 expression and function in the liver cancer [34].…”

Section: Discussionmentioning

confidence: 99%

Introducing, OncoTarget

Blagosklonny¹,

Gudkov²

2010

Oncotarget

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P53 is frequently mutated in human tumors as a novel gainoffunction to promote tumor development. Although dimeric (M340Q/L344R) influences on tetramerisation on site-specific post-translational modifications of p53, it is not clear how dimeric (M340Q/ L344R) plays a role during hepatocarcinogenesis. Herein, we reveal that P53 (N340Q/ L344R) promotes hepatocarcinogenesis through upregulation of PKM2. Mechanistically, P53 (N340Q/L344R) forms complex with CUDR and the complex binds to the promoter regions of PKM2 which enhances the expression, phosphorylation of PKM2 and its polymer formation. Thereby, the polymer PKM2 (tetramer) binds to the eleventh threonine on histone H3 that increases the phosphorylation of the eleventh threonine on histone H3 (pH3T11). Furthermore, pH3T11 blocks HDAC3 binding to H3K9Ac that prevents H3K9Ac from deacetylation and stabilizes the H3K9Ac modification. On the other hand, it also decreased trimethylation of histone H3 on the ninth lysine (H3K9me3) and increases one methylation of histone H3 on the ninth lysine (H3K9me1). Moreover, the combination of H3K9me1 and HP1 α forms more H3K9me3-HP1α complex which binds to the promoter region of Pim1, enhancing the expression of Pim1 that enhances the expression of TERT, oncogenic lncRNA HOTAIR and reduces the TERRA expression. Ultimately, P53 (N340Q/ L344R) accerlerates the growth of liver cancer cells Hep3B by activating telomerase and prolonging telomere through the cascade of P53 (N340Q/L344R)CUDRPKM2pH3T11 (H3K9me1-HP1α)-Pim1-(TERT-HOTAIR-TERRA). Understanding the novel functions of P53 (N340Q/L344R) will help in the development of new liver cancer therapeutic approaches that may be useful in a broad range of cancer types.

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Pim1 kinase synergizes with c-MYC to induce advanced prostate carcinoma

Cited by 123 publications

References 43 publications

Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid leukemia is a critical determinant of disease progression

Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid leukemia is a critical determinant of disease progression

PIM1 gene cooperates with human BCL6 gene to promote the development of lymphomas

Introducing, OncoTarget

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