Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the Flt3 gene

Autor: Robert Ploemacher, Bob Löwenberg, W. J. C. Rombouts, I. Blokland
Přispěvatelé: Hematology
Rok vydání: 2000
Předmět:
Male
Cancer Research
Myeloid
medicine.medical_treatment
Cell Count
Mice
SCID
Hematopoietic stem cell transplantation
Gene mutation
Mice
Bone Marrow
Mice
Inbred NOD
Gene Duplication
Antineoplastic Combined Chemotherapy Protocols
Life Tables
Tumor Stem Cell Assay
Aged
80 and over
Hematopoietic Stem Cell Transplantation
Hematology
Middle Aged
Prognosis
Combined Modality Therapy
Neoplasm Proteins
Treatment Outcome
medicine.anatomical_structure
Oncology
Leukemia
Myeloid
Acute Disease
Neoplastic Stem Cells
Female
Stem cell
Cell Division
psychological phenomena and processes
Adult
FLT3 Internal Tandem Duplication
Adolescent
Biology
Disease-Free Survival
Proto-Oncogene Proteins
medicine
Animals
Humans
Progenitor cell
Aged
Receptor Protein-Tyrosine Kinases
Hematopoietic Stem Cells
Survival Analysis
body regions
fms-Like Tyrosine Kinase 3
Immunology
Fms-Like Tyrosine Kinase 3
Bone marrow
Neoplasm Transplantation
Zdroj: Leukemia, 14, 675-683. Nature Publishing Group
ISSN: 1476-5551
0887-6924
Popis: 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.
Databáze: OpenAIRE
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