RUNX1 regulates phosphoinositide 3-kinase/AKT pathway: role in chemotherapy sensitivity in acute megakaryocytic leukemia

Blood. 2009 Sep 24;114(13):2744-52. doi: 10.1182/blood-2008-09-179812. Epub 2009 Jul 28.

Abstract

RUNX1 (AML1) encodes the core binding factor alpha subunit of a heterodimeric transcription factor complex which plays critical roles in normal hematopoiesis. Translocations or down-regulation of RUNX1 have been linked to favorable clinical outcomes in acute leukemias, suggesting that RUNX1 may also play critical roles in chemotherapy responses in acute leukemias; however, the molecular mechanisms remain unclear. The median level of RUNX1b transcripts in Down syndrome (DS) children with acute megakaryocytic leukemia (AMkL) were 4.4-fold (P < .001) lower than that in non-DS AMkL cases. Short hairpin RNA knockdown of RUNX1 in a non-DS AMkL cell line, Meg-01, resulted in significantly increased sensitivity to cytosine arabinoside, accompanied by significantly decreased expression of PIK3CD, which encodes the delta catalytic subunit of the survival kinase, phosphoinositide 3 (PI3)-kinase. Transcriptional regulation of PIK3CD by RUNX1 was further confirmed by chromatin immunoprecipitation and promoter reporter gene assays. Further, a PI3-kinase inhibitor, LY294002, and cytosine arabinoside synergized in antileukemia effects on Meg-01 and primary pediatric AMkL cells. Our results suggest that RUNX1 may play a critical role in chemotherapy response in AMkL by regulating the PI3-kinase/Akt pathway. Thus, the treatment of AMkL may be improved by integrating PI3-kinase or Akt inhibitors into the chemotherapy of this disease.

Publication types

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

MeSH terms

  • Child
  • Class I Phosphatidylinositol 3-Kinases
  • Core Binding Factor Alpha 2 Subunit / antagonists & inhibitors
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / physiology*
  • Cytarabine / pharmacology
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Gene Expression Profiling
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Leukemic
  • Humans
  • K562 Cells
  • Leukemia, Megakaryoblastic, Acute / enzymology
  • Leukemia, Megakaryoblastic, Acute / genetics*
  • Leukemia, Megakaryoblastic, Acute / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Oncogene Protein v-akt / genetics*
  • Oncogene Protein v-akt / metabolism
  • Phosphatidylinositol 3-Kinases / genetics*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / physiology
  • RNA, Small Interfering / pharmacology
  • Signal Transduction / genetics
  • Tumor Cells, Cultured

Substances

  • Core Binding Factor Alpha 2 Subunit
  • RNA, Small Interfering
  • RUNX1 protein, human
  • Cytarabine
  • Phosphatidylinositol 3-Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CD protein, human
  • Oncogene Protein v-akt