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Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
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Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia

Xi Jiang1,2,3, Chao Hu4,5,6, Kyle Ferchen4

  • 1Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, 45219, USA. xjiang@coh.org.

Nature Communications
|December 14, 2017
PubMed

Insights

New compounds selectively suppress TET1 transcription, inhibiting TET1-high acute myeloid leukemia (AML) cell viability and progression. These TET1 inhibitors show promise as effective AML therapies, even with standard chemotherapy.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Acute myeloid leukemia (AML) therapy effectiveness is limited.
  • Ten-eleven translocation 1 (TET1) is a key oncoprotein in AML progression.
  • Targeting TET1 offers a potential therapeutic strategy for AML.

Purpose of the Study:

  • To identify and evaluate compounds that suppress TET1 transcription and inhibit TET1-high AML.
  • To investigate the therapeutic potential of targeting the STAT/TET1 axis in AML.

Main Methods:

  • Data analysis and drug screening to identify TET1 suppressors.
  • In vitro cell viability assays and in vivo AML progression studies.
  • Analysis of compound interactions with STAT3/5 transcriptional activators.

Main Results:

  • NSC-311068 and NSC-370284 selectively suppressed TET1 transcription and 5-hydroxymethylcytosine (5hmC) modification.
  • These compounds inhibited viability in TET1-high AML, including specific subtypes.
  • UC-514321, an analog of NSC-370284, showed enhanced therapeutic effects in vivo, prolonging survival.
  • Compounds target STAT3/5, repress TET1 expression, and synergize with chemotherapy.

Conclusions:

  • Selective TET1 inhibitors, like NSC-370284 and UC-514321, demonstrate significant therapeutic potential for TET1-high AML.
  • Targeting the STAT/TET1 axis represents a promising strategy for novel AML treatments.
  • These inhibitors offer a new avenue for combination therapy with existing AML treatments.

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