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- Title
Characterization of FLT3-ITD<sup>mut</sup> acute myeloid leukemia: molecular profiling of leukemic precursor cells.
- Authors
Travaglini, Serena; Angelini, Daniela Francesca; Alfonso, Valentina; Guerrera, Gisella; Lavorgna, Serena; Divona, Mariadomenica; Nardozza, Anna Maria; Consalvo, Maria Irno; Fabiani, Emiliano; De Bardi, Marco; Neri, Benedetta; Forghieri, Fabio; Marchesi, Francesco; Paterno, Giovangiacinto; Cerretti, Raffaella; Barragan, Eva; Fiori, Valentina; Dominici, Sabrina; Del Principe, Maria Ilaria; Venditti, Adriano
- Abstract
Acute myeloid leukemia (AML) with FLT3-ITD mutations (FLT3-ITDmut) remains a therapeutic challenge, with a still high relapse rate, despite targeted treatment with tyrosine kinase inhibitors. In this disease, the CD34/CD123/CD25/CD99+ leukemic precursor cells (LPCs) phenotype predicts for FLT3-ITD-positivity. The aim of this study was to characterize the distribution of FLT3-ITD mutation in different progenitor cell subsets to shed light on the subclonal architecture of FLT3-ITDmut AML. Using high-speed cell sorting, we sequentially purified LPCs and CD34+ progenitors in samples from patients with FLT3-ITDmut AML (n = 12). A higher FLT3-ITDmut load was observed within CD34/CD123/CD25/CD99+ LPCs, as compared to CD34+ progenitors (CD123+/−,CD25−,CD99low/−) (p = 0.0005) and mononuclear cells (MNCs) (p < 0.0001). This was associated with significantly increased CD99 mean fluorescence intensity in LPCs. Significantly higher FLT3-ITDmut burden was also observed in LPCs of AML patients with a small FLT3-ITDmut clones at diagnosis. On the contrary, the mutation burden of other myeloid genes was similar in MNCs, highly purified LPCs and/or CD34+ progenitors. Treatment with an anti-CD99 mAb was cytotoxic on LPCs in two patients, whereas there was no effect on CD34+ cells from healthy donors. Our study shows that FLT3-ITD mutations occur early in LPCs, which represent the leukemic reservoir. CD99 may represent a new therapeutic target in FLT3-ITDmut AML.
- Subjects
ACUTE myeloid leukemia; GENETIC mutation; PROTEIN-tyrosine kinases; PROGENITOR cells; FLUORESCENCE
- Publication
Blood Cancer Journal, 2020, Vol 10, Issue 8, pN.PAG
- ISSN
2044-5385
- Publication type
Article
- DOI
10.1038/s41408-020-00352-9