Characterization ofFLT3-ITD(mut)acute myeloid leukemia: molecular profiling of leukemic precursor cells
| Autor: | Travaglini, S, Angelini, DF, Alfonso, V, Guerrera, G, Lavorgna, S, Divona, M, Nardozza, AM, Consalvo, MI, Fabiani, E, De Bardi, M, Neri, B, Forghieri, F, Marchesi, F, Paterno, G, Cerretti, R, Barragan, E, Fiori, V, Dominici, S, Del Principe, MI, Venditti, A, Battistini, L, Arcese, W, Lo-Coco, F, Voso, MT, Ottone, T |
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| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | BLOOD CANCER JOURNAL r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe instname |
| ISSN: | 2044-5385 |
| Popis: | Acute myeloid leukemia (AML) withFLT3-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 forFLT3-ITD-positivity. The aim of this study was to characterize the distribution ofFLT3-ITD mutation in different progenitor cell subsets to shed light on the subclonal architecture ofFLT3-ITD(mut)AML. Using high-speed cell sorting, we sequentially purified LPCs and CD34+ progenitors in samples from patients withFLT3-ITD(mut)AML (n = 12). A higherFLT3-ITD(mut)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 higherFLT3-ITD(mut)burden was also observed in LPCs of AML patients with a smallFLT3-ITD(mut)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 thatFLT3-ITD mutations occur early in LPCs, which represent the leukemic reservoir. CD99 may represent a new therapeutic target inFLT3-ITD(mut)AML. |
| Databáze: | OpenAIRE |
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