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

Abstract

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 ...

c-Myc inhibition decreases CIP2A and reduces BCR-ABL1 tyrosine kinase activity in chronic myeloid leukemia

“…9 In AML cell lines and primary cells, 10058-F4 has been shown to inhibit growth, induce cell cycle arrest and cause differentiation.…”

“…6,7 Many malignancies, including CML, are associated with inhibition of protein phosphatase 2A (PP2A). 8,9 A novel protein inhibitor of PP2A, cancerous inhibitor of PP2A (CIP2A, KIAA1525) is associated with poor outcome in many malignancies. In CML, CIP2A protein level at chronic phase diagnosis is a prospective biomarker of disease progression in imatinib-treated CML patients.…”

Expression of cancerous inhibitor of protein phosphatase 2A in human triple negative breast cancer correlates with tumor survival, invasion and autophagy

“…CIP2A is a widespread oncogenic factor in human neoplasms (4)(5)(6)(7)(8)(9)3). Similar to the Ras oncogene, CIP2A is required for anchorage-independent cell growth and malignant transformation of human cells (4).…”

“…Previous studies have shown that CIP2A serves a critical role in the progression of several cancer types, including head and neck squamous cell carcinoma, oral squamous cell carcinoma, oesophageal squamous cell carcinoma, colon, gastric, breast, prostate, tongue, lung, cervical cancer and acute myeloid leukaemia (3)(4)(5)(6)(7)(8)(9). In 2009, Côme et al (10) demonstrated that CIP2A is associated with clinical aggressivity in human breast cancer and promotes the malignant growth of breast cancer cells (10).…”

Cyanobacterial Toxins of the Laurentian Great Lakes, their Toxicological Effects, and Numerical Limits in Drinking Water

“…At a high dose, MCs cause massive changes in cell morphology through cytoskeletal rearrangements and oxidative stress, leading to loss of cell-to-cell adhesion and cell death [175][176][177]. In a chronic model of low level exposure, constant mild PP2A inhibition leads to reprogramming of the cell, runaway cell growth, and tumor production, analogous to the effects of endogenous human protein CIP2A (cancerous inhibitor of PP2A) associated with breast and lung cancer [178][179][180][181].…”