title: PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells.
abstract: The success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML) depends on the requirement for BCR-ABL1 kinase activity in CML progenitors. However, CML quiescent HSCs are TKI resistant and represent a BCR-ABL1 kinase-independent disease reservoir. Here we have shown that persistence of leukemic HSCs in BM requires inhibition of the tumor suppressor protein phosphatase 2A (PP2A) and expression--but not activity--of the BCR-ABL1 oncogene. Examination of HSCs from CML patients and healthy individuals revealed that PP2A activity was suppressed in CML compared with normal HSCs. TKI-resistant CML quiescent HSCs showed increased levels of BCR-ABL1, but very low kinase activity. BCR-ABL1 expression, but not kinase function, was required for recruitment of JAK2, activation of a JAK2/β-catenin survival/self-renewal pathway, and inhibition of PP2A. PP2A-activating drugs (PADs) markedly reduced survival and self-renewal of CML quiescent HSCs, but not normal quiescent HSCs, through BCR-ABL1 kinase-independent and PP2A-mediated inhibition of JAK2 and β-catenin. This led to suppression of human leukemic, but not normal, HSC/progenitor survival in BM xenografts and interference with long-term maintenance of BCR-ABL1-positive HSCs in serial transplantation assays. Targeting the JAK2/PP2A/β-catenin network in quiescent HSCs with PADs (e.g., FTY720) has the potential to treat TKI-refractory CML and relieve lifelong patient dependence on TKIs.
authors.forename: Paolo
authors.initials: P
authors.lastname: Neviani
authors.forename: Jason G
authors.initials: JG
authors.lastname: Harb
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Oaks
authors.forename: Ramasamy
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authors.lastname: Santhanam
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Walker
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Ellis
authors.forename: Gregory
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authors.lastname: Ferenchak
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Dorrance
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Paisie
authors.forename: Anna M
authors.initials: AM
authors.lastname: Eiring
authors.forename: Yihui
authors.initials: Y
authors.lastname: Ma
authors.forename: Hsiaoyin C
authors.initials: HC
authors.lastname: Mao
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Mark
authors.initials: M
authors.lastname: Wunderlich
authors.forename: Philippa C
authors.initials: PC
authors.lastname: May
authors.forename: Chaode
authors.initials: C
authors.lastname: Sun
authors.forename: Sahar A
authors.initials: SA
authors.lastname: Saddoughi
authors.forename: Jacek
authors.initials: J
authors.lastname: Bielawski
authors.forename: William
authors.initials: W
authors.lastname: Blum
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Klisovic
authors.forename: Janelle A
authors.initials: JA
authors.lastname: Solt
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Claudia S
authors.initials: CS
authors.lastname: Huettner
authors.forename: Steffen
authors.initials: S
authors.lastname: Koschmieder
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Holyoake
authors.forename: Steven
authors.initials: S
authors.lastname: Devine
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Ramiro
authors.initials: R
authors.lastname: Garzon
authors.forename: Besim
authors.initials: B
authors.lastname: Ogretmen
authors.forename: Ralph B
authors.initials: RB
authors.lastname: Arlinghaus
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman
authors.forename: Peter
authors.initials: P
authors.lastname: Hokland
authors.forename: Denis-Claude
authors.initials: DC
authors.lastname: Roy
authors.forename: Dragana
authors.initials: D
authors.lastname: Milojkovic
authors.forename: Jane
authors.initials: J
authors.lastname: Apperley
authors.forename: John M
authors.initials: JM
authors.lastname: Goldman
authors.forename: Alistair
authors.initials: A
authors.lastname: Reid
authors.forename: James C
authors.initials: JC
authors.lastname: Mulloy
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhatia
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D020536:Enzyme Activators / Q000494:pharmacology; D000068876:Fingolimod Hydrochloride; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology; D011409:Propylene Glycols / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D060449:Wnt Signaling Pathway; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D020536:Enzyme Activators; D011409:Propylene Glycols; D047428:Protein Kinase Inhibitors; D051176:beta Catenin; D016044:Fusion Proteins, bcr-abl; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D054648:Protein Phosphatase 2; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine