PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells

J Clin Invest. 2013 Oct;123(10):4144-57. doi: 10.1172/JCI68951. Epub 2013 Sep 3.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm
  • Enzyme Activators / pharmacology
  • Fingolimod Hydrochloride
  • Fusion Proteins, bcr-abl / metabolism
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / enzymology
  • Humans
  • Janus Kinase 2 / metabolism
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Mice
  • Mice, Transgenic
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / enzymology
  • Propylene Glycols / pharmacology
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Phosphatase 2 / metabolism*
  • Sphingosine / analogs & derivatives
  • Sphingosine / pharmacology
  • Wnt Signaling Pathway
  • Xenograft Model Antitumor Assays
  • beta Catenin / metabolism

Substances

  • Antineoplastic Agents
  • Enzyme Activators
  • Propylene Glycols
  • Protein Kinase Inhibitors
  • beta Catenin
  • Fusion Proteins, bcr-abl
  • JAK2 protein, human
  • Janus Kinase 2
  • Protein Phosphatase 2
  • Fingolimod Hydrochloride
  • Sphingosine