Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Notch3-regulated microRNAs impair CXCR4-dependent maturation of thymocytes allowing maintenance and progression of T-ALL

Oncogene volume 43, pages 2535–2547 (2024)Cite this article

Subjects

A Correction to this article was published on 25 July 2024

This article has been updated

Abstract

Malignant transformation of T-cell progenitors causes T-cell acute lymphoblastic leukemia (T-ALL), an aggressive childhood lymphoproliferative disorder. Activating mutations of Notch, Notch1 and Notch3, have been detected in T-ALL patients. In this study, we aimed to deeply characterize hyperactive Notch3-related pathways involved in T-cell dynamics within the thymus and bone marrow to propose these processes as an important step in facilitating the progression of T-ALL. We previously generated a transgenic T-ALL mouse model (N3-ICtg) demonstrating that aberrant Notch3 signaling affects early thymocyte maturation programs and leads to bone marrow infiltration by CD4+CD8+ (DP) T cells that are notably, Notch3highCXCR4high. Newly, our in vivo results suggest that an anomalous immature thymocyte subpopulation, such as CD4−CD8− (DN) over-expressing CD3ɛ, but with low CXCR4 expression, dominates N3-ICtg thymus-resident DN subset in T-ALL progression. MicroRNAs might be of significance in T-ALL pathobiology, however, whether required for leukemia maintenance is not fully understood. The selection of specific DN subsets demonstrates the inverse correlation between CXCR4 expression and a panel of Notch3-deregulated miRNAs. Interestingly, we found that within DN thymocyte subset hyperactive Notch3 inhibits CXCR4 expression through the cooperative effects of miR-139-5p and miR-150-5p, thus impinging on thymocyte differentiation with accumulation of DNCD3ɛ+CXCR4− cells. These data point out that deregulation of Notch3 in T-ALL, besides its role in sustaining dissemination of abnormal DP T cells, as we previously demonstrated, could play a role in selecting specific DN immature T cells within the thymus, thus impeding T cell development, to facilitate T-ALL progression inside the bone marrow.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Notch3 expands the immature CD4−CD8−CD3ε+/high thymocytes.
Fig. 2: Notch3-induced CXCR4 downmodulation impairs DN T-cells maturation and migration.
Fig. 3: CXCR4 expression inversely correlates with miR139-5p and miR150-5p in transgenic DNCD3ε+ thymocytes.
Fig. 4: The cooperative function of miR-150-5p and miR-139-5p reduces CXCR4 expression in murine and human T-ALL cell lines.
Fig. 5: Analysis of RBPjk occupancy in human and murine miR-139-5p promoter.
Fig. 6: CXCR4 expression is inversely correlated to miR-150 and miR-139 in patient-derived xenograft (PDTALL).
Fig. 7: In vivo CD45 labeling reveals the high level of vasculature-associated DNCD3ε+CD25+ in N3-ICtg thymus possibly invading transgenic bone marrow.
Fig. 8: Graphical representation of the dynamic changes subverting the transgenic N3-ICtg thymus at 12–14 weeks of age.

Similar content being viewed by others

Data availability

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.

Change history

References

  1. Chiaretti S, Li X, Gentleman R, Vitale A, Vignetti M, Mandelli F, et al. Gene expression profile of adult T-cell acute lymphocytic leukemia identifies distinct subsets of patients with different response to therapy and survival. Blood. 2004;103:2771–8.

    Article  CAS  PubMed  Google Scholar 

  2. Matthijssens F, Sharma ND, Nysus M, Nickl CK, Kang H, Perez DR, et al. RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia. J Clin Investig. 2021;131:e141566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. McMahon CM, Luger SM. Relapsed T cell ALL: current approaches and new directions. Curr Hematol Malig Rep. 2019;14:83–93.

    Article  PubMed  Google Scholar 

  4. Scupoli MT, Donadelli M, Cioffi F, Rossi M, Perbellini O, Malpeli G, et al. Bone marrow stromal cells and the upregulation of interleukin-8 production in human T-cell acute lymphoblastic leukemia through the CXCL12/CXCR4 axis and the NF-kappaB and JNK/AP-1 pathways. Haematologica. 2008;93:524–32.

    Article  CAS  PubMed  Google Scholar 

  5. Chiaretti S, Zini G, Bassan R. Diagnosis and subclassification of acute lymphoblastic leukemia. Mediterr J Hematol Infect Dis. 2014;6:e2014073.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Chiang MY, Radojcic V, Maillard I. Oncogenic Notch signaling in T-cell and B-cell lymphoproliferative disorders. Curr Opin Hematol. 2016;23:362–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bernasconi-Elias P, Hu T, Jenkins D, Firestone B, Gans S, Kurth E, et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene. 2016;35:6077–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Takebe N, Miele L, Harris PJ, Jeong W, Bando H, Kahn M, et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol. 2015;12:445–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tsaouli G, Barbarulo A, Vacca A, Screpanti I, Felli MP. Molecular Mechanisms of Notch Signaling in Lymphoid Cell Lineages Development: NF-kappaB and Beyond. Adv Exp Med Biol. 2020;1227:145–64.

    Article  CAS  PubMed  Google Scholar 

  10. Radtke F, Fasnacht N, Macdonald HR. Notch signaling in the immune system. Immunity. 2010;32:14–27.

    Article  CAS  PubMed  Google Scholar 

  11. Janas ML, Turner M. Stromal cell-derived factor 1alpha and CXCR4: newly defined requirements for efficient thymic beta-selection. Trends Immunol 2010;31:370–6.

    Article  CAS  PubMed  Google Scholar 

  12. Tsaouli G, Ferretti E, Bellavia D, Vacca A, Felli MP. Notch/CXCR4 partnership in acute lymphoblastic leukemia progression. J Immunol Res. 2019;2019:5601396.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Trampont PC, Tosello-Trampont AC, Shen Y, Duley AK, Sutherland AE, Bender TP, et al. CXCR4 acts as a costimulator during thymic beta-selection. Nat Immunol. 2010;11:162–70.

    Article  CAS  PubMed  Google Scholar 

  14. Bellavia D, Campese AF, Alesse E, Vacca A, Felli MP, Balestri A, et al. Constitutive activation of NF-kappaB and T-cell leukemia/lymphoma in Notch3 transgenic mice. EMBO J. 2000;19:3337–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Felli MP, Vacca A, Calce A, Bellavia D, Campese AF, Grillo R, et al. PKC theta mediates pre-TCR signaling and contributes to Notch3-induced T-cell leukemia. Oncogene. 2005;24:992–1000.

    Article  CAS  PubMed  Google Scholar 

  16. Vacca A, Felli MP, Palermo R, Di Mario G, Calce A, Di Giovine M, et al. Notch3 and pre-TCR interaction unveils distinct NF-kappaB pathways in T-cell development and leukemia. EMBO J. 2006;25:1000–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Franciosa G, Diluvio G, Gaudio FD, Giuli MV, Palermo R, Grazioli P, et al. Prolyl-isomerase Pin1 controls Notch3 protein expression and regulates T-ALL progression. Oncogene. 2016;35:4741–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Del Gaizo M, Sergio I, Lazzari S, Cialfi S, Pelullo M, Screpanti I, et al. MicroRNAs as modulators of the immune response in T-Cell acute lymphoblastic leukemia. Int J Mol Sci. 2022;23:829.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Pitt LA, Tikhonova AN, Hu H, Trimarchi T, King B, Gong Y, et al. CXCL12-producing vascular endothelial niches control acute T Cell leukemia maintenance. Cancer Cell. 2015;27:755–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jost TR, Borga C, Radaelli E, Romagnani A, Perruzza L, Omodho L, et al. Role of CXCR4-mediated bone marrow colonization in CNS infiltration by T cell acute lymphoblastic leukemia. J Leukoc Biol. 2016;99:1077–87.

    Article  CAS  PubMed  Google Scholar 

  21. Kadakia T, Tai X, Kruhlak M, Wisniewski J, Hwang IY, Roy S, et al. E-protein-regulated expression of CXCR4 adheres preselection thymocytes to the thymic cortex. J Exp Med. 2019;216:1749–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Maroni P, Bendinelli P, Matteucci E, Desiderio MA. HGF induces CXCR4 and CXCL12-mediated tumor invasion through Ets1 and NF-kappaB. Carcinogenesis. 2007;28:267–79.

    Article  CAS  PubMed  Google Scholar 

  23. Wang J, Wang H, Cai J, Du S, Xin B, Wei W, et al. Artemin regulates CXCR4 expression to induce migration and invasion in pancreatic cancer cells through activation of NF-kappaB signaling. Exp Cell Res. 2018;365:12–23.

    Article  CAS  PubMed  Google Scholar 

  24. Cheng M, Yang J, Zhao X, Zhang E, Zeng Q, Yu Y, et al. Circulating myocardial microRNAs from infarcted hearts are carried in exosomes and mobilise bone marrow progenitor cells. Nat Commun. 2019;10:959.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Alsayed R, Khan AQ, Ahmad F, Ansari AW, Alam MA, Buddenkotte J, et al. Epigenetic regulation of CXCR4 signaling in cancer pathogenesis and progression. Semin Cancer Biol. 2022;86:697–708.

    Article  CAS  PubMed  Google Scholar 

  26. Portella L, Bello AM, Scala S. CXCL12 signaling in the tumor microenvironment. Adv Exp Med Biol. 2021;1302:51–70.

    Article  CAS  PubMed  Google Scholar 

  27. Dawidowska M, Jaksik R, Drobna M, Szarzynska-Zawadzka B, Kosmalska M, Sedek L, et al. Comprehensive investigation of miRNome identifies Novel Candidate miRNA-mRNA interactions implicated in T-cell acute lymphoblastic leukemia. Neoplasia. 2019;21:294–310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wallaert A, Van Loocke W, Hernandez L, Taghon T, Speleman F, Van Vlierberghe P. Comprehensive miRNA expression profiling in human T-cell acute lymphoblastic leukemia by small RNA-sequencing. Sc Rep. 2017;7:7901.

    Article  Google Scholar 

  29. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kumar V, Palermo R, Talora C, Campese AF, Checquolo S, Bellavia D, et al. Notch and NF-kB signaling pathways regulate miR-223/FBXW7 axis in T-cell acute lymphoblastic leukemia. Leukemia. 2014;28:2324–35.

    Article  CAS  PubMed  Google Scholar 

  31. Li X, Sanda T, Look AT, Novina CD, von Boehmer H. Repression of tumor suppressor miR-451 is essential for NOTCH1-induced oncogenesis in T-ALL. J Exp Med. 2011;208:663–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mansour MR, Sanda T, Lawton LN, Li X, Kreslavsky T, Novina CD, et al. The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia. J Exp Med. 2013;210:1545–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Shu Y, Wang Y, Lv WQ, Peng DY, Li J, Zhang H, et al. ARRB1-Promoted NOTCH1 Degradation Is Suppressed by OncomiR miR-223 in T-cell Acute Lymphoblastic Leukemia. Cancer Res. 2020;80:988–98.

    Article  CAS  PubMed  Google Scholar 

  34. Gebarowska K, Mroczek A, Kowalczyk JR, Lejman M. MicroRNA as a prognostic and diagnostic marker in T-cell acute lymphoblastic leukemia. Int J Mol Sci. 2021;22:5317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rasaiyaah J, Georgiadis C, Preece R, Mock U, Qasim W. TCRalphabeta/CD3 disruption enables CD3-specific antileukemic T cell immunotherapy. JCI Insight. 2018;3:e99442.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Yui MA, Rothenberg EV. Developmental gene networks: a triathlon on the course to T cell identity. Nat Rev Immunol. 2014;14:529–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dos Santos NR, Ghysdael J, Tran Quang C. The TCR/CD3 complex in leukemogenesis and as a therapeutic target in T-cell acute lymphoblastic leukemia. Adv Biol Regul. 2019;74:100638.

    Article  PubMed  Google Scholar 

  38. Ferrandino F, Bernardini G, Tsaouli G, Grazioli P, Campese AF, Noce C, et al. Intrathymic Notch3 and CXCR4 combinatorial interplay facilitates T-cell leukemia propagation. Oncogene. 2018;37:6285–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Plotkin J, Prockop SE, Lepique A, Petrie HT. Critical role for CXCR4 signaling in progenitor localization and T cell differentiation in the postnatal thymus. J Immunol. 2003;171:4521–7.

    Article  CAS  PubMed  Google Scholar 

  40. Petrie HT, Zuniga-Pflucker JC. Zoned out: functional mapping of stromal signaling microenvironments in the thymus. Annu Rev Immunol. 2007;25:649–79.

    Article  CAS  PubMed  Google Scholar 

  41. Coustan-Smith E, Mullighan CG, Onciu M, Behm FG, Raimondi SC, Pei D, et al. Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol. 2009;10:147–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Shiraz P, Jehangir W, Agrawal V. T-Cell Acute Lymphoblastic Leukemia-Current Concepts in Molecular Biology and Management. Biomedicines. 2021;9:1621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wallaert A, Durinck K, Taghon T, Van Vlierberghe P, Speleman F. T-ALL and thymocytes: a message of noncoding RNAs. J Hematol Oncol. 2017;10:66.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Yi J, Gao ZF. MicroRNA-9-5p promotes angiogenesis but inhibits apoptosis and inflammation of high glucose-induced injury in human umbilical vascular endothelial cells by targeting CXCR4. Int J Biol Macromol. 2019;130:1–9.

    Article  CAS  PubMed  Google Scholar 

  45. Qin L, Deng HY, Chen SJ, Wei W, Zhang YT. miR-139 acts as a tumor suppressor in T-cell acute lymphoblastic leukemia by targeting CX chemokine receptor 4. Am J Transl Res. 2017;9:4059–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Liu Z, Ye P, Wang S, Wu J, Sun Y, Zhang A, et al. MicroRNA-150 protects the heart from injury by inhibiting monocyte accumulation in a mouse model of acute myocardial infarction. Circ Cardiovasc Genet. 2015;8:11–20.

    Article  CAS  PubMed  Google Scholar 

  47. Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. Elife. 2015;4:e05005.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Zhang N, Qu Y, Qin B. Sodium butyrate ameliorates non-alcoholic fatty liver disease by upregulating miR-150 to suppress CXCR4 expression. Clin Exp Pharm Physiol. 2021;48:1125–36.

    Article  CAS  Google Scholar 

  49. Tano N, Kim HW, Ashraf M. microRNA-150 regulates mobilization and migration of bone marrow-derived mononuclear cells by targeting Cxcr4. PLoS ONE. 2011;6:e23114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. He Y, Jiang X, Chen J. The role of miR-150 in normal and malignant hematopoiesis. Oncogene. 2014;33:3887–93.

    Article  CAS  PubMed  Google Scholar 

  51. Ghisi M, Corradin A, Basso K, Frasson C, Serafin V, Mukherjee S, et al. Modulation of microRNA expression in human T-cell development: targeting of NOTCH3 by miR-150. Blood. 2011;117:7053–62.

    Article  CAS  PubMed  Google Scholar 

  52. Agnusdei V, Minuzzo S, Frasson C, Grassi A, Axelrod F, Satyal S, et al. Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts. Leukemia. 2014;28:278–88.

    Article  CAS  PubMed  Google Scholar 

  53. Minuzzo S, Agnusdei V, Pinazza M, Amaro AA, Sacchetto V, Pfeffer U, et al. Targeting NOTCH1 in combination with antimetabolite drugs prolongs life span in relapsed pediatric and adult T-acute lymphoblastic leukemia xenografts. Exp Hematol Oncol. 2023;12:76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gao X, Qin S, Wu Y, Chu C, Jiang B, Johnson RH, et al. Nuclear PFKP promotes CXCR4-dependent infiltration by T cell acute lymphoblastic leukemia. J Clin Investig. 2021;131:e143119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sciume G, De Angelis G, Benigni G, Ponzetta A, Morrone S, Santoni A, et al. CX3CR1 expression defines 2 KLRG1+ mouse NK-cell subsets with distinct functional properties and positioning in the bone marrow. Blood. 2011;117:4467–75.

    Article  CAS  PubMed  Google Scholar 

  56. Ruscher R, Hogquist KA. Intravenous Labeling and Analysis of the Content of Thymic Perivascular Spaces. Bio Protoc. 2018;8:e2757.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Martins VC, Busch K, Juraeva D, Blum C, Ludwig C, Rasche V, et al. Cell competition is a tumour suppressor mechanism in the thymus. Nature. 2014;509:465–70.

    Article  CAS  PubMed  Google Scholar 

  58. Abdulla HD, Alserihi R, Flensburg C, Abeysekera W, Luo MX, Gray DHD, et al. Overexpression of Lmo2 initiates T-lymphoblastic leukemia via impaired thymocyte competition. J Exp Med. 2023;220:e20212383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rothenberg EV. Programming for T-lymphocyte fates: modularity and mechanisms. Genes Dev. 2019;33:1117–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kyriakidis I, Kyriakidis K, Tsezou A. MicroRNAs and the diagnosis of childhood acute lymphoblastic leukemia: systematic review, meta-analysis and re-analysis with novel small RNA-seq tools. Cancers. 2022;14:3976.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Nair RA, Verma VK, Beevi SS, Rawoof A, Alexander LE, Prasad ER, et al. MicroRNA signatures in blood or bone marrow distinguish subtypes of pediatric acute lymphoblastic leukemia. Transl Oncol. 2020;13:100800.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Tian XP, Xie D, Huang WJ, Ma SY, Wang L, Liu YH, et al. A gene-expression-based signature predicts survival in adults with T-cell lymphoblastic lymphoma: a multicenter study. Leukemia. 2020;34:2392–404.

    Article  CAS  PubMed  Google Scholar 

  63. Tian XP, Huang WJ, Huang HQ, Liu YH, Wang L, Zhang X, et al. Prognostic and predictive value of a microRNA signature in adults with T-cell lymphoblastic lymphoma. Leukemia. 2019;33:2454–65.

    Article  CAS  PubMed  Google Scholar 

  64. Abdulla H, Vo A, Shields BJ, Davies TJ, Jackson JT, Alserihi R, et al. T-ALL can evolve to oncogene independence. Leukemia. 2021;35:2205–19.

    Article  CAS  PubMed  Google Scholar 

  65. Maroder M, Bellavia D, Vacca A, Felli MP, Screpanti I. The thymus at the crossroad of neuroimmune interactions. Ann N. Y Acad Sci. 2000;917:741–7.

    Article  CAS  PubMed  Google Scholar 

  66. Grazioli P, Orlando A, Giordano N, Noce C, Peruzzi G, Abdollahzadeh B, et al. Notch-Signaling Deregulation Induces Myeloid-Derived Suppressor Cells in T-Cell Acute Lymphoblastic Leukemia. Front Immunol. 2022;13:809261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Grazioli P, Felli MP, Screpanti I, Campese AF. The mazy case of Notch and immunoregulatory cells. J Leukoc Biol. 2017;102:361–8.

    Article  CAS  PubMed  Google Scholar 

  68. Barbarulo A, Grazioli P, Campese AF, Bellavia D, Di Mario G, Pelullo M, et al. Notch3 and canonical NF-kappaB signaling pathways cooperatively regulate Foxp3 transcription. J Immunol. 2011;186:6199–206.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to acknowledge Ilaria Pia Caporale, Federica Squillante, Noemi Martina Cantale Aeo and Marco Crisci for contribution to the experimental work, Laura Fasano for animal care assistance and the Flow Cytometry Facility at Center for Life Nano-Neuro Science, IIT, for support and technical advice.

Funding

This study was founded by the Sapienza University grants, Avvio alla Ricerca: (AR222181616D9D01) to SKP; Avvio alla Ricerca (AR1181643646B258) to GT; (AR123188AF112A64) to IS; Ateneo 2021 (RP12117A63FBA27C), 2022 (RP122181642E92CE), 2023 (RP123188F3C01EB7) to MPF; Ateneo 2021 (RM12117A71419448) to AFC; MIUR PNR 2015-2020 ARS01_00432, PROGEMA to IScre and by Italian Ministry of Education, University and Research – Dipartimenti di Eccellenza - L. 232/2016; Horizon 2020 (PH118164340087CF) to IScre. The manuscript has been supported by the Croatian Science Foundation grant number HRZZ IP-2020-02-2431(I. Scre and MPF).

Author information

Author notes

  1. These authors contributed equally: Ilaria Sergio, Claudia Varricchio, Sandesh Kumar Patel.

  2. These authors jointly supervised this work: Antonio Francesco Campese, Maria Pia Felli.

Authors and Affiliations

  1. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy

    Ilaria Sergio, Zein Mersini Besharat, Federica Campolo, Mary Anna Venneri & Maria Pia Felli

  2. Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy

    Claudia Varricchio, Sandesh Kumar Patel, Eleonora Russo, Sonia Coni, Giovanni Bernardini, Isabella Screpanti & Antonio Francesco Campese

  3. Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy

    Martina Del Gaizo & Silvia Lai

  4. Division of Hematology & Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York NY, USA

    Andrea Orlando

  5. Center for Life Nano-Neuro Science, IIT, Rome, Italy

    Giovanna Peruzzi

  6. A.O.R.N. dei colli Monaldi V., Napoli, Italy

    Francesca Ferrandino

  7. Department of Medical-Surgical Science and Translational Medicine, Sapienza University of Rome, Rome, Italy

    Georgia Tsaouli

  8. Ph.D School of Applied Medical-Surgical Sciences, Department of Biology, University of Rome “Tor Vergata”, Rome, Italy

    Daniele Peluso

  9. Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy

    Donatella Del Bufalo

  10. Department of Surgery Oncology and Gastroenterology, University of Padua, Padua, Italy

    Stefano Indraccolo & Sonia Minuzzo

  11. Basic and Translational Oncology Unit, Istituto Oncologico Veneto IOV-IRCCS, Padua, Italy

    Stefano Indraccolo

  12. Hematology Section, Department of Medicine and Surgery, and S. Maria Della Misericordia Hospital Perugia, CREO, Perugia, Italy

    Roberta La Starza

Authors
  1. Ilaria Sergio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Claudia Varricchio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sandesh Kumar Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martina Del Gaizo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eleonora Russo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrea Orlando
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Giovanna Peruzzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Francesca Ferrandino
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Georgia Tsaouli
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sonia Coni
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Daniele Peluso
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Zein Mersini Besharat
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Federica Campolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Mary Anna Venneri
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Donatella Del Bufalo
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Silvia Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Stefano Indraccolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Sonia Minuzzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Roberta La Starza
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Giovanni Bernardini
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Isabella Screpanti
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Antonio Francesco Campese
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Maria Pia Felli
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

IS, CV and SKP designed and performed the experiments, analyzed the data and wrote the first draft of the paper. MDG, AO, FF, and GT performed the experiments. DP, SL, RLS and ZMB analyzed the data. FC, MAV, GB, DDB, ER, SI, SC and SM collaborated on the experiments and analyzed the data. GP did all the sorting experiments. IScre critically revised the manuscript. MPF and AFC supervised the experiments, analyzed the data, and wrote the manuscript. The authors read and approved the final manuscript.

Corresponding author

Correspondence to Maria Pia Felli.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Ethics approval and consent statement

RNA samples were obtained from Patient-derived xenografts (PDTALL) after informed consent from all individual participants collected and following the Declaration of Helsinki. All the procedures were approved by the Ethics Committee with the protocol number AIEOP-BFM ALL 2009.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sergio, I., Varricchio, C., Patel, S.K. et al. Notch3-regulated microRNAs impair CXCR4-dependent maturation of thymocytes allowing maintenance and progression of T-ALL. Oncogene 43, 2535–2547 (2024). https://doi.org/10.1038/s41388-024-03079-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-024-03079-0

Search

Advanced search

Quick links