Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia

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Interleukin 7 (IL-7) and its receptor, formed by IL-7Rα (encoded by IL7R) and γc, are essential for normal T-cell development and homeostasis. Here we show that IL7R is an oncogene mutated in T-cell acute lymphoblastic leukemia (T-ALL). We find that 9% of individuals with T-ALL have somatic gain-of-function IL7R exon 6 mutations. In most cases, these IL7R mutations introduce an unpaired cysteine in the extracellular juxtamembrane-transmembrane region and promote de novo formation of intermolecular disulfide bonds between mutant IL-7Rα subunits, thereby driving constitutive signaling via JAK1 and independently of IL-7, γc or JAK3. IL7R mutations induce a gene expression profile partially resembling that provoked by IL-7 and are enriched in the T-ALL subgroup comprising TLX3 rearranged and HOXA deregulated cases. Notably, IL7R mutations promote cell transformation and tumor formation. Overall, our findings indicate that IL7R mutational activation is involved in human T-cell leukemogenesis, paving the way for therapeutic targeting of IL-7R–mediated signaling in T-ALL.

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Figure 1: IL7R exon 6 somatic mutations in pediatric T-ALL.
Figure 2: Molecular signatures associated with IL7R mutations in T-ALL.
Figure 3: IL7R mutations induce constitutive signaling in a manner that is independent of IL-7, γc and JAK3 and relies on disulfide bond promotion of homodimer formation.
Figure 4: IL7R mutations induce cell-cycle progression, increase cell viability and promote growth factor independence.
Figure 5: In vivo tumorigenic effect of IL7R mutations.
Figure 6: Targeting IL7R mutants using JAK-STAT pathway inhibitors.

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  1. 1

    Jiang, Q. et al. Cell biology of IL-7, a key lymphotrophin. Cytokine Growth Factor Rev. 16, 513–533 (2005).

  2. 2

    Fry, T.J. & Mackall, C.L. The many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance. J. Immunol. 174, 6571–6576 (2005).

  3. 3

    von Freeden-Jeffry, U. et al. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J. Exp. Med. 181, 1519–1526 (1995).

  4. 4

    Peschon, J.J. et al. Early lymphocyte expansion is severely impaired in interleukin 7 receptor–deficient mice. J. Exp. Med. 180, 1955–1960 (1994).

  5. 5

    Puel, A., Ziegler, S.F., Buckley, R.H. & Leonard, W.J. Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency. Nat. Genet. 20, 394–397 (1998).

  6. 6

    Roifman, C.M., Zhang, J., Chitayat, D. & Sharfe, N. A partial deficiency of interleukin-7Rα is sufficient to abrogate T-cell development and cause severe combined immunodeficiency. Blood 96, 2803–2807 (2000).

  7. 7

    Lundmark, F. et al. Variation in interleukin 7 receptor α chain (IL7R) influences risk of multiple sclerosis. Nat. Genet. 39, 1108–1113 (2007).

  8. 8

    Hafler, D.A. et al. Risk alleles for multiple sclerosis identified by a genomewide study. N. Engl. J. Med. 357, 851–862 (2007).

  9. 9

    Rich, B.E., Campos-Torres, J., Tepper, R.I., Moreadith, R.W. & Leder, P. Cutaneous lymphoproliferation and lymphomas in interleukin 7 transgenic mice. J. Exp. Med. 177, 305–316 (1993).

  10. 10

    Abraham, N. et al. Haploinsufficiency identifies STAT5 as a modifier of IL-7–induced lymphomas. Oncogene 24, 5252–5257 (2005).

  11. 11

    Laouar, Y., Crispe, I.N. & Flavell, R.A. Overexpression of IL-7Rα provides a competitive advantage during early T-cell development. Blood 103, 1985–1994 (2004).

  12. 12

    Touw, I. et al. Interleukin-7 is a growth factor of precursor B and T acute lymphoblastic leukemia. Blood 75, 2097–2101 (1990).

  13. 13

    Barata, J.T., Cardoso, A.A., Nadler, L.M. & Boussiotis, V.A. Interleukin-7 promotes survival and cell cycle progression of T-cell acute lymphoblastic leukemia cells by down-regulating the cyclin-dependent kinase inhibitor p27(kip1). Blood 98, 1524–1531 (2001).

  14. 14

    Barata, J.T., Keenan, T.D., Silva, A., Boussiotis, V.A. & Cardoso, A.A. Common γ chain-signaling cytokines promote proliferation of T-cell acute lymphoblastic leukemia. Haematologica 89, 1459–1467 (2004).

  15. 15

    González-García, S. et al. CSL-MAML-dependent Notch1 signaling controls T lineage-specific IL-7Rα gene expression in early human thymopoiesis and leukemia. J. Exp. Med. 206, 779–791 (2009).

  16. 16

    Weng, A.P. et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306, 269–271 (2004).

  17. 17

    Flex, E. et al. Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. J. Exp. Med. 205, 751–758 (2008).

  18. 18

    Shochat, C. et al. Gain-of-function mutations in interleukin-7 receptor-α (IL7R) in childhood acute lymphoblastic leukemias. J. Exp. Med. 208, 901–908 (2011).

  19. 19

    Kovanen, P.E. et al. Analysis of γ c-family cytokine target genes. Identification of dual-specificity phosphatase 5 (DUSP5) as a regulator of mitogen-activated protein kinase activity in interleukin-2 signaling. J. Biol. Chem. 278, 5205–5213 (2003).

  20. 20

    Homminga, I. et al. Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T-cell acute lymphoblastic leukemia. Cancer Cell 19, 484–497 (2011).

  21. 21

    Ferrando, A.A. et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell 1, 75–87 (2002).

  22. 22

    van Grotel, M. et al. Prognostic significance of molecular-cytogenetic abnormalities in pediatric T-ALL is not explained by immunophenotypic differences. Leukemia 22, 124–131 (2008).

  23. 23

    Bene, M.C. et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia 9, 1783–1786 (1995).

  24. 24

    Jeong, E.G. et al. Somatic mutations of JAK1 and JAK3 in acute leukemias and solid cancers. Clin. Cancer Res. 14, 3716–3721 (2008).

  25. 25

    Walters, D.K. et al. Activating alleles of JAK3 in acute megakaryoblastic leukemia. Cancer Cell 10, 65–75 (2006).

  26. 26

    Barata, J.T. et al. Activation of PI3K is indispensable for interleukin 7-mediated viability, proliferation, glucose use, and growth of T cell acute lymphoblastic leukemia cells. J. Exp. Med. 200, 659–669 (2004).

  27. 27

    Maser, R.S. et al. Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers. Nature 447, 966–971 (2007).

  28. 28

    Palomero, T. et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat. Med. 13, 1203–1210 (2007).

  29. 29

    Silva, A. et al. PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability. J. Clin. Invest. 118, 3762–3774 (2008).

  30. 30

    Gutierrez, A. et al. High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood 114, 647–650 (2009).

  31. 31

    Jotta, P.Y. et al. Negative prognostic impact of PTEN mutation in pediatric T-cell acute lymphoblastic leukemia. Leukemia 24, 239–242 (2010).

  32. 32

    O'Neil, J. et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to γ-secretase inhibitors. J. Exp. Med. 204, 1813–1824 (2007).

  33. 33

    Thompson, B.J. et al. The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia. J. Exp. Med. 204, 1825–1835 (2007).

  34. 34

    Zuurbier, L. et al. NOTCH1 and/or FBXW7 mutations predict for initial good prednisone response but not for improved outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on DCOG or COALL protocols. Leukemia 24, 2014–2022 (2010).

  35. 35

    Kim, K. et al. Characterization of an interleukin-7–dependent thymic cell line derived from a p53(−/−) mouse. J. Immunol. Methods 274, 177–184 (2003).

  36. 36

    Lu, X., Gross, A.W. & Lodish, H.F. Active conformation of the erythropoietin receptor: random and cysteine-scanning mutagenesis of the extracellular juxtamembrane and transmembrane domains. J. Biol. Chem. 281, 7002–7011 (2006).

  37. 37

    Kjaer, S., Kurokawa, K., Perrinjaquet, M., Abrescia, C. & Ibanez, C.F. Self-association of the transmembrane domain of RET underlies oncogenic activation by MEN2A mutations. Oncogene 25, 7086–7095 (2006).

  38. 38

    Burke, C.L. & Stern, D.F. Activation of Neu (ErbB-2) mediated by disulfide bond-induced dimerization reveals a receptor tyrosine kinase dimer interface. Mol. Cell. Biol. 18, 5371–5379 (1998).

  39. 39

    Yoda, A. et al. Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia. Proc. Natl. Acad. Sci. USA 107, 252–257 (2010).

  40. 40

    Liu, X. et al. Crucial role of interleukin-7 in T helper type 17 survival and expansion in autoimmune disease. Nat. Med. 16, 191–197 (2010).

  41. 41

    Kovanen, P.E. & Leonard, W.J. Cytokines and immunodeficiency diseases: critical roles of the γ(c)-dependent cytokines interleukins 2, 4, 7, 9, 15, and 21, and their signaling pathways. Immunol. Rev. 202, 67–83 (2004).

  42. 42

    Ridder, A., Skupjen, P., Unterreitmeier, S. & Langosch, D. Tryptophan supports interaction of transmembrane helices. J. Mol. Biol. 354, 894–902 (2005).

  43. 43

    Russ, W.P. & Engelman, D.M. The GxxxG motif: a framework for transmembrane helix-helix association. J. Mol. Biol. 296, 911–919 (2000).

  44. 44

    Al-Rawi, M.A., Mansel, R.E. & Jiang, W.G. Interleukin-7 (IL-7) and IL-7 receptor (IL-7R) signalling complex in human solid tumours. Histol. Histopathol. 18, 911–923 (2003).

  45. 45

    Izon, D.J. et al. Loss of function of the homeobox gene Hoxa-9 perturbs early T-cell development and induces apoptosis in primitive thymocytes. Blood 92, 383–393 (1998).

  46. 46

    Mullighan, C.G. et al. CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature 471, 235–239 (2011).

  47. 47

    Mullighan, C.G. et al. Rearrangement of CRLF2 in B-progenitor– and Down syndrome–associated acute lymphoblastic leukemia. Nat. Genet. 41, 1243–1246 (2009).

  48. 48

    Kleppe, M. et al. Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia. Nat. Genet. 42, 530–535 (2010).

  49. 49

    Van Vlierberghe, P. et al. PHF6 mutations in T-cell acute lymphoblastic leukemia. Nat. Genet. 42, 338–342 (2010).

  50. 50

    Amendola, M., Venneri, M.A., Biffi, A., Vigna, E. & Naldini, L. Coordinate dual-gene transgenesis by lentiviral vectors carrying synthetic bidirectional promoters. Nat. Biotechnol. 23, 108–116 (2005).

  51. 51

    Jensen, M.M., Jorgensen, J.T., Binderup, T. & Kjaer, A. Tumor volume in subcutaneous mouse xenografts measured by microCT is more accurate and reproducible than determined by 18F-FDG-microPET or external caliper. BMC Med. Imaging 8, 16 (2008).

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We are grateful to the subjects and their families for providing the specimens for this study. We thank S. Walsh (University of Maryland) for helpful discussions on the IL7R transmembrane domain; K. Czarra and M. Karwan for animal technical assistance; A. Silva, I. Antunes, A. Melão and J. Buijs-Gladdines for experimental support; P. Vandenabeele for kindly providing the WEHI3B cell line; and J. O'Shea for providing Jak3−/− bone marrow and CP-690550. This work was supported by grants from Fundação para a Ciência e a Tecnologia (FCT; PTDC/SAU-OBD/104816/2008, J.T.B.), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; 08/10034-1, J.A.Y.) and the intramural program of the National Cancer Institute, US National Institutes of Health (NIH) (S.K.D.). P.P.Z. and A.B.S. have Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) PhD scholarships. L.M.S. has a postdoctoral fellowship; D.R., B.A.C. and N.C. have PhD scholarships, and M.C.S. had a Bolsa de Investigação (BI) fellowship, all from the FCT. L.Z. was supported by a grant (2007-012) from the foundation Children Cancer-Free (Stichting Kinderen Kankervrij; KiKa).

Author information

J.T.B. and J.A.Y. conceived and supervised the study. J.T.B., J.A.Y., S.K.D. and J.P.M. designed the experiments. J.T.B. coordinated the different contributions and wrote the paper. J.A.Y., S.K.D., J.P.M., A.A.F., W.L., D.R. and P.P.Z. contributed to the writing of portions of the paper. P.P.Z., D.R., W.L., L.Z., M.C.S., M.P., J.T., J.A.H., A.B.S., B.A.C., L.M.S. and N.C. performed experiments. J.T.B., J.A.Y., S.K.D., J.P.M., A.A.F., P.P.Z., D.R., W.L., M.C.S., A.B.S., N.C. and L.M.S. analyzed the data. M.L.T., J.K., R.P., M.H. and S.R.B. contributed reagents or clinical information.

Correspondence to João T Barata.

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Zenatti, P., Ribeiro, D., Li, W. et al. Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia. Nat Genet 43, 932–939 (2011) doi:10.1038/ng.924

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