c-Met inhibition in a HOXA9/Meis1 model of CN-AML

Nuala M Mulgrew, Laura M J Kettyle, Joanne M. Ramsey, Susan Cull, Laura J. Smyth, Danielle M. Mervyn, Janet J Bijl, Alexander Thompson

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

BACKGROUND: Hematopoiesis is a paradigm for developmental processes, hierarchically organized, with stem cells at its origin. Hematopoietic stem cells (HSCs) replenish progenitor and precursor cells of multiple lineages, which normally differentiate into short-lived mature circulating cells. Hematopoiesis has provided insight into the molecular basis of tissue homeostasis and malignancy. Malignant hematopoiesis, in particular acute myeloid leukemia (AML), results from impaired development or differentiation of HSCs and progenitors. Co-overexpression of HOX and TALE genes, particularly the HOXA cluster and MEIS1, is associated with AML. Clinically relevant models of AML are required to advance drug development for an aging patient cohort.

RESULTS: Molecular analysis identified altered gene, microRNA, and protein expression in HOXA9/Meis1 leukemic bone marrow compared to normal controls. A candidate drug screen identified the c-Met inhibitor SU11274 for further analysis. Altered cell cycle status, apoptosis, differentiation, and impaired colony formation were shown for SU11274 in AML cell lines and primary leukemic bone marrow.

CONCLUSIONS: The clonal HOXA9/Meis1 AML model is amenable to drug screening analysis. The data presented indicate that human AML cells respond in a similar manner to the HOXA9/Meis1 cells, indicating pre-clinical relevance of the mouse model.

Original languageEnglish
Pages (from-to)172-81
Number of pages10
JournalDevelopmental dynamics : an official publication of the American Association of Anatomists
Volume243
Issue number1
Early online date04 Dec 2013
DOIs
Publication statusPublished - Jan 2014

Keywords

  • Animals
  • Disease Models, Animal
  • Homeodomain Proteins
  • Humans
  • Indoles
  • Leukemia, Myeloid, Acute
  • Mice
  • MicroRNAs
  • Neoplasm Proteins
  • Piperazines
  • Proto-Oncogene Proteins c-met
  • Sulfonamides

Fingerprint

Dive into the research topics of 'c-Met inhibition in a HOXA9/Meis1 model of CN-AML'. Together they form a unique fingerprint.

Cite this