Characterization of FLT3-ITDmut acute myeloid leukemia: molecular profiling of leukemic precursor cells

Serena Travaglini, Daniela Francesca Angelini, Valentina Alfonso, Gisella Guerrera, Serena Lavorgna, Mariadomenica Divona, Anna Maria Nardozza, Maria Irno Consalvo, Emiliano Fabiani, Marco De Bardi, Benedetta Neri, Fabio Forghieri, Francesco Marchesi, Giovangiacinto Paterno, Raffaella Cerretti, Eva Barragan, Valentina Fiori, Sabrina Dominici, Maria Ilaria Del Principe, Adriano VendittiLuca Battistini, William Arcese, Francesco Lo-Coco, Maria Teresa Voso, Tiziana Ottone

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number85
JournalBlood Cancer Journal
Volume10
Issue number8
DOIs
Publication statusPublished - Aug 1 2020

ASJC Scopus subject areas

  • Hematology
  • Oncology

Fingerprint

Dive into the research topics of 'Characterization of FLT3-ITD<sup>mut</sup> acute myeloid leukemia: molecular profiling of leukemic precursor cells'. Together they form a unique fingerprint.

Cite this