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Acute Leukemias

Prognostic significance of FLT3 mutational status and expression levels in MLL-AF4+ and MLL-germline acute lymphoblastic leukemia

Leukemia volume 26, pages 2360–2366 (2012)Cite this article

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Abstract

There is barely any information about the prognostic significance of FLT3 expression and mutational status in cytogenetically distinct subgroups of acute lymphoblastic leukemia (ALL). We analyzed the presence of FLT3-tyrosine kinase domain (TKD) and FLT3-internal tandem duplication (ITD) mutations as well as FLT3 expression levels in 54 newly diagnosed patients with B-ALL (n=49) or T-ALL (n=5). All B/T-ALL samples tested negative for the presence of FLT3-TKD or FLT3-ITD. None of the T-ALL and E2A-PBX1+ B-ALL overexpressed FLT3. In contrast, mainly MLL-AF4+ B-ALL but also ETV6-RUNX1+, BCR-ABL+ or B-ALL displaying normal cytogenetics exhibited significantly higher FLT3 expression levels than normal bone marrow, supporting that aberrantly increased transcription of FLT3, rather than activating FLT3 mutations, contributes to the pathogenesis of these B-ALL. Using the median FLT3 expression as cut-off value we found that high-level FLT3 expression is associated with an extremely poor 1-year overall survival (OS; 0 vs 71%; P=0.002) and disease-free survival (DFS; 0 vs 43%; P=0.03) in MLL-AF4+ B-ALL but not in MLL-germline B-ALL. Cox regression analysis with OS/DFS as end points showed that age>14 years and high-level FLT3 expression were independent prognostic factors when all ALL patients were analyzed together. Importantly, when the MLL-AF4+ B-ALL subgroup was analyzed separately, high-level FLT3 expression was the only independent prognostic factor for OS and treatment outcome. These findings indicate that high FLT3 expression identifies MLL-AF4+ ALL patients at very high risk of treatment failure and poor survival, emphasizing the value of ongoing/future clinical trials for FLT3 inhibitors.

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Acknowledgements

PM was supported by the Junta de Andalucía/FEDER (P08-CTS-3678), the FIS/FEDER (PI10/00449), the MICINN (Fondo Especial del Estado para Dinamización de la Economía y Empleo-PLE-2009–0111) and the Fundación ‘Spanish Association Against Cancer′/Junta Provincial de Albacete (CI110023). CB was supported by the FIS/FEDER (CP07/0005 and PI11/00119). RM was supported by the FIS/FEDER (CA10/01332). MCC and MG-D were supported by the FIS/FEDER (CA11/00243).

AUTHOR CONTRIBUTIONS

MCC, MTG-C, MG and PM were involved in theconception and design, collection and/or assembly of the data, financial support, data analysis and interpretation and manuscript writing. CEL-J, C R-M, AM, MES, MA, JDG-S, CB, RM, FR, JNR, PG, MR, RG-D and JLF were involved in provision of patient samples, clinical data collection and interpretation, and also in the collection and/or assembly of the data.

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Author notes

  1. M C Chillón and M T Gómez-Casares: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, University Hospital of Salamanca and Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain

    M C Chillón, M E Sarasquete, M Alcoceba & M González-Díaz

  2. Servicio de Hematología/Unidad de Investigación Hospital Universitario de Gran Canaria Dr. Negrin, Las Palmas de Gran Canaria, Spain

    M T Gómez-Casares, C E López-Jorge & C Rodriguez-Medina

  3. Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain

    A Molines & J D G-S Miguel

  4. Centre Pfizer-Universidad de Granada-Junta de Andalucía for Genomics and Oncological Research (GENyO), Granada, Spain

    C Bueno, R Montes & P Menendez

  5. Hospital de León and Ibiomed, Universidad de León, León, Spain

    F Ramos

  6. Hospital Juan Ramón Jiménez, Huelva, Spain

    J N Rodríguez

  7. Hospital Miguel Servet, Zaragoza, Spain

    P Giraldo

  8. Hospital Niño Jesús, Madrid, Spain

    M Ramírez

  9. Hospital Clínico de Málaga, Málaga, Spain

    R García-Delgado

  10. Hospital Virgen de Arrixaca, Murcia, Spain

    J L Fuster

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  1. M C Chillón
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Correspondence to M C Chillón or P Menendez.

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Chillón, M., Gómez-Casares, M., López-Jorge, C. et al. Prognostic significance of FLT3 mutational status and expression levels in MLL-AF4+ and MLL-germline acute lymphoblastic leukemia. Leukemia 26, 2360–2366 (2012). https://doi.org/10.1038/leu.2012.161

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