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Kim, R.1; Tueur, G.2; Delecourt, M.2; Boissel, N.3; Feroul, M.1; Latiri, M.2; Vilarese, P.2; Hippolyte, G.1; Tesio, M.1; Andrieu, G.1; Ifrah, N.4; Petit, A.5; Dombret, H.6; Macintyre, E.1, 2; Asnafi, V.1, 2; Lhermitte, L.1, 2

doi: 10.1097/
Simultaneous Sessions I: Modeling and therapeutic targeting in acute lymphoblastic leukemia I

1Institut Necker-Enfants Malades (INEM), Institut National de recherche Médicale (INSERM) U1151, Université Paris Descartes Sorbonne Cité

2Clinical Lab Haematology, APHP Necker Enfants Malades

3Clinical Haematology department, APHP Hôpital Saint-Louis, Paris

4Clinical Haematology, CHU Angers, Angers

5Clinical Haematology, APHP (Hopital Armand Trousseau)

6Clinical Haematology, APHP Hôpital Saint-Louis, Paris, France

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Normal T-cell development is supported by cytokine signaling with IL7 as key player. This is highlighted by the absence of T-cells in gamma-chain SCID-patients. T-ALL represents a heterogeneous disease characterized by expansion of immature T-cells blocked in their differentiation. Despite therapeutic improvements, it remains associated with a poor prognosis mainly due to relapses. This results in a medical need for new therapeutic approaches. Several studies reported the deregulation of IL7R signaling notably via genomic alterations accounting for ˜30% of T-ALL. In keeping with this, preclinical models supported the possibility to target the IL7R-pathway (IL7Rp) in IL7Rp-mutated T-ALL using pharmacological JAK inhibitors such as ruxolitinib. Moreover, ex vivo culture of primary T-ALL samples requires addition of IL7 cytokine in culture medium to support leukemic cell survival. Altogether, this data supports a strong dependency of T-ALL on IL7R signalling. However, the question of which T-ALL patients may benefit from JAK inhibitors remains unclear.

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We aimed to investigate surface IL7R (sIL7R) expression and mutational status of IL7Rp in T-ALL, and to identify a readout for patient JAK inhibitor sensitivity.

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159 T-ALL samples were prospectively analyzed by FACS for IL7R expression. Genetic data of IL7R pathway genes (IL7R, JAK1/2, STAT5) were assessed on 87 adult T-ALL enrolled in the ongoing GRAALL-2014 trial by targeted-sequencing. 21 patient derived xenograft (PDX) T-ALL were generated for ex vivo studies including i) phosphoprotein flow analysis of pSTAT5 upon IL7 stimulation and JAK inhibition, ii) apoptosis assay by Annexin V-PI staining, and iii) proliferation assay using Celltrace.

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sIL7R was expressed at early stages of normal T-cell development, downregulated during the cortical stage, and up-regulated at the mature stage. In T-ALL, sIL7R was expressed in 84/159 cases (53%). We found IL7Rp mutations in 29% of cases and all IL7Rmut cases expressed sIL7R defining 3 classes of T-ALL depending on sIL7R expression and mutational status of IL7Rp: IL7R-/WT, IL7R+/WT, IL7R+/mut. IL7R+ T-ALLs were mainly of immature non-ETP, cortical and TCRgd phenotype. These data support frequent and abnormal expression of sIL7R in T-ALL as regard to normal expression pattern in thymocytes.

sIL7R expression was always associated with functional signaling of the receptor: pSTAT5 was activated upon IL7 exposure and abrogated by the addition of ruxolitinib in both normal thymocytes and PDX T-ALL. Constitutive STAT5 phosphorylation was observed in IL7R+/mut but not in IL7R+/WT PDX T-ALL. However, pSTAT5 activation reached similar levels in both IL7R+/mut and IL7R+/WT PDX T-ALL upon IL7 exposure regardless of their mutational status, which was completely reversed by ruxolitinib addition. Ex vivo treatment of PDX T-ALL with increasing doses of ruxolitinib induced apoptosis and cytostatic effect in both IL7R+/WT and IL7R+/mut PDX T-ALL.

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IL7Rp genes are mutated in 29% in T-ALL and sIL7R is expressed in 53% of cases. Ruxolitinib induces apoptosis and impairs cell proliferation in sIL7R+ T-ALL irrespective of IL7Rp mutational status. Our data shows that sensitivity to JAK inhibitors is determined by the expression of IL7R regardless of the IL7Rp genomic status. IL7R expression is a readout for JAK inhibitors sensitivity, and provides a fast and accurate companion theranostic tool using flow-cytometry.

Copyright © 2019 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.