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Rapid childhood T-ALL growth in xenograft models correlates with mature phenotype and NF-κB pathway activation but not with poor prognosis

Leukemia volume 29, pages 977–980 (2015)Cite this article

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T-cell acute lymphoblastic leukemia (T-ALL) is characterized by the uncontrolled growth of T-cell precursors in various sites such as bone marrow, blood, thymus or lymph nodes. Primary human T-ALL cells can be functionally studied using their transplantation into immunodeficient mice or their ex vivo coculture with murine stromal cells.1, 2, 3, 4 Nonetheless, T-ALL growth in these two systems remains highly variable across T-ALL samples raising questions about the clinical and biological significance of such variability. As a comparison, in B-cell ALL (B-ALL) and in acute myeloid leukemia, a correlation between leukemic engraftment into immunodeficient mice and patient outcome has been described.5, 6 The aims of the present work were to determine the relationships between T-ALL features at diagnosis and T-ALL growth in xenografts, to unravel the molecular mechanisms underlying T-ALL growth variability and to uncover any potential targetable pathway to inhibit T-ALL growth. Hereafter, we show that rapid T-ALL growth in xenografts correlates with SIL-TAL1 deletion, mature phenotype but not with poor prognosis. Moreover, NF-κB pathway activation underlies human T-ALL differential growth in immunodeficient mice, thus highlighting NF-κB as a potentially targetable pathway to inhibit human T-ALL growth.

Among diagnostic clinical and biological characteristics, neither patient gender, age<10, mediastinal enlargement, CNS involvement, pleural effusion, EGIL classification nor abnormal karyotype was associated with a short TTL (Supplementary table S2), whereas a trend for a short TTL was observed for patients with a WBC>median WBC (=146 G/L; P=0.06, Supplementary table S2). Furthermore, SIL-TAL1 deletion and surface expression of CD8 or TCRαβ on ⩾20% leukemic cells were associated with a short TTL (Supplementary table S2). The correlation of TTL with clinical outcome was also tested. With a median follow-up of 33 months (range 13–86 months) among surviving patients, the 3-year progression-free survival in the short TTL group (61%) was not statistically different from the no/long group (81%) (P=0.14) (Figure 1e). Although a predictive value might have emerged from a larger cohort and/or a more homogeneous treatment protocol, two other reasons may explain this T-ALL characteristic. Despite their short TTL, SIL-TAL1 T-ALL do not display any adverse prognosis.7 Furthermore, clinical proliferation—evaluated by WBC counts—is not associated with poor prognosis in pediatric T-ALL unlike B-ALL.8 Patients' outcome—which mirrors T-ALL chemosensitivity—and TTL—which relates to the growth capacity in xenografts—are two distinct and disconnected features of the disease. Unlike B-ALL, TTL in xenografts cannot be used for preclinical stratification in T-ALL.6

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Acknowledgements

We thank the donors for agreeing to the use of their cells for research and the clinical teams of the Hôpital A Trousseau and Hôpital R Debré in Paris, IHOP in Lyon and Institut Gustave Roussy in Villejuif for collecting samples. We are grateful to the LSHL lab for advice and comments during the work and to William Hempel for his help in the editing of the manuscript. Mouse work was facilitated by Christophe Joubert and Julien Tilliet from the animal colony facility of IRCM. Micro-array analysis was performed in the GENOM’IC platform of Institut Cochin, Paris with Florent Dumont and Franck Letourneur. We thank the microscopy facility at the CEA-IRCM institute for technical advice and in particular Lamya Irbah and Thierry Kortulewsky. This work was supported by INSERM, CEA, Université Paris Diderot and Université Paris Sud, Institut National du Cancer (INCA), Cancéropôle d’Ile de France, Région Ile de France, the Ligue Nationale contre le Cancer (LNCC, équipe labellisée) and the Association Laurette Fugain. SP was supported by INCA and LNCC. XC was supported by INCA.

Author contributions

SP and XC designed and performed experiments; analyzed data and wrote the paper. FP coordinated, directed the study and wrote the paper. PB provided patient samples, clinical data and participated in discussions. BU, C B-G, and VB performed experiments and gave advices. HL, TL, AB, J L-P, AP, FB, SA provided patient samples and clinical data.

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Author notes

  1. F Baleydier

    Present address: 13Current address: Department of Paediatric Haemato-oncology, Bristol Royal Hospital for Children, University Hospitals Bristol, Bristol, BS2 8BJ, UK,

  2. S Poglio and X Cahu: These authors contributed equally to this work.

Authors and Affiliations

  1. Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), DSV-IRCM-SCSR-LSHL, Equipe labellisée Ligue Nationale contre le Cancer, Fontenay-aux-Roses, France

    S Poglio, X Cahu, B Uzan, P Ballerini & F Pflumio

  2. INSERM UMR967, Fontenay-aux-Roses, France

    S Poglio, X Cahu, B Uzan, P Ballerini & F Pflumio

  3. Université Paris Diderot, Sorbonne Paris Cité, Fontenay-aux-Roses, France

    S Poglio, X Cahu, B Uzan, P Ballerini & F Pflumio

  4. Université Paris-Sud, Fontenay-aux-Roses, France

    S Poglio, X Cahu, B Uzan, P Ballerini & F Pflumio

  5. CNRS UMR8104, Paris, France

    C Besnard-Guérin & V Baud

  6. Université Paris Descartes, Sorbonne Paris Cité, Paris, France

    C Besnard-Guérin & V Baud

  7. INSERM U1016, Institut Cochin, Paris, France

    C Besnard-Guérin & V Baud

  8. Assistance Publique—Hôpitaux de Paris, Service d’hématologie pédiatrique, Hôpital A. Trousseau et Université Pierre et Marie Curie, Paris, France

    H Lapillonne, J Landman-Parker, A Petit & P Ballerini

  9. Assistance Publique—Hôpitaux de Paris, Service d’hématologie pédiatrique, Hôpital Robert Debré, Paris, France

    T Leblanc & A Baruchel

  10. Institut d’Hématologie et Oncologie Pédiatrique, Hospices Civils de Lyon et Université Claude Bernard, Lyon 1, France

    F Baleydier

  11. Service d’Hématologie, Institut Gustave Roussy, Villejuif, France

    S Amsellem

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  1. S Poglio
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Correspondence to S Poglio or F Pflumio.

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Poglio, S., Cahu, X., Uzan, B. et al. Rapid childhood T-ALL growth in xenograft models correlates with mature phenotype and NF-κB pathway activation but not with poor prognosis. Leukemia 29, 977–980 (2015). https://doi.org/10.1038/leu.2014.317

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