Biological Characteristics and Prognosis of Adult Acute Myeloid Leukemia With Internal Tandem Duplications in the Flt3 Gene

Leukemia. 2000 Apr;14(4):675-83. doi: 10.1038/sj.leu.2401731.

Abstract

Internal tandem duplications of the FIt3 gene (FIt3/ITDs) are present in about 18% of all AML cases and are therefore one of the most frequent somatic gene mutations in AML. Little is known about the role of FIt3/ITDs in leukemogenesis or their clinical relevance. In this study we compared 18 samples with FIt3/ITDs and 63 AML samples without these mutations with respect to clinical prognosis, cytokine responsiveness, progenitor cell content and repopulation in the NOD/SCID mouse. We found that in patients with a mutation CR rates are reduced (P=0.03) and relapse rates are increased (P=0.01), indicating the prognostic importance of FIt3/ITDs. This is also emphasized by the finding that in patients under the age of 60 years, as well as in older patients the event-free survival was more unfavorable for the mutant patients (P=0.003 and P=0.03, respectively). At diagnosis FIt3/ITD and non-mutant AML bone marrow samples did not differ in their progenitor/stem cell frequencies. Cobblestone area forming cell (CAFC) subsets showed a similar frequency distribution in mutant and non-mutant samples. In 7-day liquid cultures, FIt3/ITD samples showed a reduced growth in response to a variety of myeloid growth factors. In contrast, FIt3/ITD samples displayed a higher ability to engraft the NOD/SCID bone marrow with leukemic cells. Together these data show that the FIt3/ITD represents an important diagnostic marker for patient prognosis, and that the presence of these mutations is associated with altered proliferative ability of progenitors in vivo and in vitro.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Bone Marrow / pathology
  • Cell Count
  • Cell Division / genetics
  • Combined Modality Therapy
  • Disease-Free Survival
  • Female
  • Gene Duplication*
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Leukemia, Myeloid / genetics*
  • Leukemia, Myeloid / mortality
  • Leukemia, Myeloid / pathology
  • Leukemia, Myeloid / therapy
  • Life Tables
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Middle Aged
  • Neoplasm Proteins / genetics*
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / pathology
  • Prognosis
  • Proto-Oncogene Proteins / genetics*
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Survival Analysis
  • Treatment Outcome
  • Tumor Stem Cell Assay
  • fms-Like Tyrosine Kinase 3

Substances

  • Neoplasm Proteins
  • Proto-Oncogene Proteins
  • FLT3 protein, human
  • Flt3 protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • fms-Like Tyrosine Kinase 3