Download CML Biology Session Saturday – PP2A as a

Saturday June 11th session PM – CML Biology
The tumor suppressor PP2A as a therapeutic target for eradication of TKI resistant Ph+
leukemic stem cells
As we know, the success of the TKI’s depends on the addiction of the PH+ CML progenitor cells to
BCR ABL1 kinase activity. However, CML quiescent HSC’s are TKI resistant and unfortunately represent
an active disease reservoir. The working hypothesis for this study is that drug resistance of the quiescent
HSC depends on inhibition of the tumor suppressor protein phosphatase 2A (PP2A). PP2A can be
activated by FTY720 a drug that targets CML but not normal progenitors. The aim of this study is to
investigate the mechanisms controlling survival/self-renewal of quiescent HSC. They compared HSC’s
from 68 CML patients and 12 healthy donors, the biologic importance of PP2A inhibition and
pharmacologic PP2A activation on their survival/self renewal was assessed by BM bone marrow) serial
transplantations, CFSE and annexin-V staining; LTC-IC and CFC/replating assays, lentiviral
shRNA/cDNA-transduction; LEF/TCF and proximity-ligation assays; western blot, confocal microscopy
and FACS analyses (note from C.A. Simoneau, I do not expect typical lay patients to understand this, I
barely understand all the testing techniques, but rest assured the scientists in the audience were
impressed with the thorough testing used here to help prove the hypothesis). The results are interesting,
as it seemed to point out a way that leads to inhibiting PP2A (which is not what we want, PP2A should not
be inhibited). They observed increased BCR ABL1 expression with impaired kinase activity in quiescent
CML HSC, in which BCR ABL1 per se is required for induction of JAK2 that subsequently activated betacatenin and inhibited PP2A. In fact, PP2A was suppressed in CML but not normal CD34+/CD38/CD90+HSCs. Further more this showed that survival and self/renewal of the CML quiescent cells but not
the normal HSC’s were markedly reduced with FTY720 and/or its non-immunosuppressive (S)-FTY7200Me derivative through a BCR ABL1 kinase independent and PP2A mediated JAK2 and beta-catenin
inhibition. Very importantly FTY720 strongly diminished BCR ABL1+ LT=HSC frequency in serial BM
transplantation assays. The exciting conclusion by the authors for this study is that the BCR ABL1 kinase
independent JAK2/-beta catenin signaling in quiescent HSCs can be pharmacologically targeted with
FTY720 and its derivative, which may lead to a cessation of lifelong patient dependence on TKI’s.
Note from C.A. Simoneau, FTY720 is currently available on the market as Gilenya (fingolimod) for
treatment in multiple sclerosis and is marketed by Novartis.
Note: I have copied data directly from the abstract to ensure that it was not misinterpreted.
The references for this abstract are:
Abstract 0520
THE TUMOR SUPPRESSOR PP2A AS A THERAPEUTIC TARGET FOR ERADICATION OF TKIRESISTANT PH LEUKEMIC STEM CELLS
Author
MD, PhD Perrotti, D, The Ohio State University, Columbus, United States of America (Presenting author)
Co-author(s)
Neviani, P, The Ohio State University, Columbus, United States of America
Harb, J, The Ohio State University, Columbus, United States of America
Oaks, J, The Ohio State University, Columbus, United States of America
Santhanam, R, The Ohio State University, Columbus, United States of America
Walker, C, The Ohio State University, Columbus, United States of America
Paisie, C, The Ohio State University, Columbus, United States of America
Eiring, A, The Ohio State University, Columbus, United States of America
Ma, Y, The Ohio State University, Columbus, United States of America
Mao, H, The Ohio State University, Columbus, United States of America
Zhang, B, City of Hope, Duarte, United States of America
Sun, C, City University of New York, Flushing, United States of America
Saddoughi, S, Medical University of South Carolina, Charleston, United States of America
Bielawski, J, Medical University of South Carolina, Charleston, United States of America
Blum, W, The Ohio State University, Columbus, United States of America
Klisovic, R, The Ohio State University, Columbus, United States of America
Byrd, J, The Ohio State University, Columbus, United States of America
Volinia, S, Universita degli Studi di Ferrara, Ferrara, Italy
Cortes, J, MD Anderson Cancer Center, Houston, United States of America
Huettner, C, Harvard Medical School, Boston, United States of America
Koschmieder, S, University of Muenster, Muenster, Germany
Holyoake, T, University of Glasgow, Glasgow, United Kingdom
Devine, S, The Ohio State University, Columbus, United States of America
Caligiuri, M, The Ohio State University, Columbus, United States of America
Croce, C, The Ohio State University, Columbus, United States of America
Ogretmen, B, Medical University of South Carolina, Charleston, United States of America
Bittman, R, City University of New York, Flushing, United States of America
Hokland, P, Aarhus University, Aarhus, Denmark
Roy, D, University of Montreal, Montreal, Canada
Chen, C, The Ohio State University, Columbus, United States of America
Marcucci, G, The Ohio State University, Columbus, United States of America
Arlinghaus, R, MD Anderson Cancer Center, Houston, United States of America
Bhatia, R, City of Hope, Duarte, United States of America