Forskolin vs. T315I

[Guest guest]

This one is complicated because it involves networks of inhibitors of

activators of inhibitors of the sort that characterize twenty first century

molecular cell biology (making lots of biologists happy, and the rest of us

crazy) At some point I hope that a) all these molecules will be given names

I can both pronounce and remember; and someone will create a virtual

interactive 3D model of the cells that will allow me to cruise through them

and learn visually, viscerally, how this incredibly complicated world really

works.

For now, though, back on planet earth: BCR/ABL INCREASES the activity of an

enzyme called SET that turns OFF another enzyme called PP2A (grrr!) that

PROMOTES the death of cancer (including CML) cells. An herb improbably

called forskolin REACTIVATES PP2A, resulting in " growth suppression,

enhanced apoptosis, restored differentiation, impaired clonogenic potential

and decreased in vivo leukemogenesis of wild type and T315I

BCR/ABL-transformed myeloid cells. " That's a lot, for an herb - and

potentially really great, especially if it gets around the defenses of the

evil mutant BCR/ABL clone, T315I, which this abstract suggests it might.

R

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[1992] ReSETting PP2A Tumor Suppressor Activity Overcomes BCR/ABL

Leukemogenic Potential in Blast Crisis CML. Session Type: Poster Session

196-II

Paolo Neviani, Ramasamy Santhanam, Rossana Trotta, Notari, Bradley W.

Blaser, Ji-Suk Chang, Shujun Liu, Hsiaoyin Mao, J. Oaks, Denis C.

Roy, Mauro Valtieri, Bruner-Klisovic, A. Caligiuri, Clara D.

Bloomfield, Guido Marcucci, Danilo Perrotti . Dept. Microbiology, Virology,

Immunology and Medical Genetics, Div. Human Cancer Genetics, The Ohio State

University, Columbus, OH, USA; Dept. Internal Medicine, Div.

Hematology-Oncology, The Ohio State University, Columbus, OH, USA; The

Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA;

Dept. of Medicine, Div. Immunology-Hematology, Maisonneuve-Rosemont Hospital

Research Center and Universite de Montreal, Montreal, QC, Canada; Dept. of

Hematology-Oncology, Istituto Superiore di Sanita', Rome, Italy

A tight control of kinase and phosphatase activity is fundamental for normal

cell growth, survival and differentiation. The deregulated kinase activity

of the BCR/ABL oncoprotein is responsible for the emergence and maintenance

of chronic myelogenous leukemia (CML). By contrast, PP2A, a serine-threonine

phosphatase involved in the regulation of many cellular functions, was found

genetically inactivated in many types of cancer. We show here that, in

BCR/ABL-transformed cells and CD34+ CML blast crisis progenitors, the

phosphatase activity of the tumor suppressor PP2A is inhibited by the

physiological PP2A-inhibitor SET whose expression is enhanced by BCR/ABL and

increased in blast crisis CML. In imatinib-sensitive and -resistant (T315I

included) BCR/ABL+ cell lines and in CD34+ CML blast crisis cells, molecular

and/or pharmacological activation of PP2A leads to dephosphorylation of

important regulators of proliferation and survival of CML progenitors,

suppresses BCR/ABL kinase activity and promotes BCR/ABL proteasome

degradation via a mechanism that requires the SHP-1 tyrosine phosphatase

activity. Furthermore, PP2A activation achieved by shRNA-mediated SET

knock-down or PP2Ac overexpression or treatment with the PP2A activator

forskolin results in growth suppression, enhanced apoptosis, restored

differentiation, impaired clonogenic potential and decreased in vivo

leukemogenesis of wild type and T315I BCR/ABL-transformed myeloid cells.

Thus, functional inactivation of PP2A phosphatase activity is essential for

BCR/ABL leukemogenesis and, perhaps, required for transition of CML into

blast crisis.