Skip to main content

Thank you for visiting 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.

ALKATI interacts with c-Myc and promotes cancer stem cell-like properties in sarcoma


Soft tissue sarcoma (STS) is a highly malignant tumor with limited targeted therapies. A novel anaplastic lymphoma kinase (ALK) transcript, ALKATI, was identified recently and could be targeted by ALK inhibitors in melanoma. However, the clinical and functional role of aberrant ALKATI expression in STS remains unknown. Here we demonstrate that as a new ALK transcript, ALKATI is frequently found in STS. ALKATI expression correlates with a lower probability of progression-free survival in STS patients. Compared with the other ALK isoforms, ALKATI expresses not only in the cytoplasm, but also in the nucleus of sarcoma cells. Functionally, overexpression of ALKATI promoted cancer stem cell (CSC)-like properties in sarcoma cells by promoting sphere formation and upregulating the expression of stem cell markers. Moreover, the ALK inhibitors not only suppressed the oncogenic functions of ALKATI but also attenuated ALKATI-induced CSC-like properties by reducing the expression of stem cell markers such as c-Myc, ABCG2, BMI1, and OCT4 both in vitro and in vivo. Furthermore, ALKATI interacted with c-Myc and increased the binding of c-Myc to the ABCG2 promoter, resulting in the induction of stem cell-like properties. Together, these findings indicate that ALKATI may be a potential prognostic marker and therapeutic target for STS patients harboring such ALK aberrations.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6


  1. Toro JR, Travis LB, Wu HJ, Zhu K, Fletcher CD, Devesa SS. Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results program, 1978–2001: an analysis of 26,758 cases. Int J Cancer. 2006;119:2922–30.

    Article  CAS  Google Scholar 

  2. Pisters PW, Leung DH, Woodruff J, Shi W, Brennan MF. Analysis of prognostic factors in 1041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol. 1996;14:1679–89.

    Article  CAS  Google Scholar 

  3. Lewis JJ, Leung D, Heslin M, Woodruff JM, Brennan MF. Association of local recurrence with subsequent survival in extremity soft tissue sarcoma. J Clin Oncol. 1997;15:646–52.

    Article  CAS  Google Scholar 

  4. FDA Approval for Pazopanib Hydrochloride. U.S. National Institutes of Health, 2013. Accessed 28 Sep 2017.

  5. FDA approves new therapy for certain types of advanced soft tissue sarcoma. U.S. Food and Drug Administration, 2015. Accessed 18 Aug 2017.

  6. FDA approves first drug to show survival benefit in liposarcoma. U.S. Food and Drug Administration, 2016. Accessed 18 Aug 2017.

  7. FDA grants accelerated approval to new treatment for advanced soft tissue sarcoma. U.S. Food and Drug Administration, 2016. Accessed 18 Aug 2017.

  8. Sheng JY, Movva S. Systemic therapy for advanced soft tissue sarcoma. Surg Clin North Am. 2016;96:1141–56.

    Article  Google Scholar 

  9. Grande E, Bolos MV, Arriola E. Targeting oncogenic ALK: a promising strategy for cancer treatment. Mol Cancer Ther. 2011;10:569–79.

    Article  CAS  Google Scholar 

  10. Armstrong F, Lamant L, Hieblot C, Delsol G, Touriol C. TPM3-ALK expression induces changes in cytoskeleton organisation and confers higher metastatic capacities than other ALK fusion proteins. Eur J Cancer. 2007;43:640–6.

    Article  CAS  Google Scholar 

  11. Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27:4247–53.

    Article  CAS  Google Scholar 

  12. Van Roosbroeck K, Cools J, Dierickx D, Thomas J, Vandenberghe P, Stul M, et al. ALK-positive large B-cell lymphomas with cryptic SEC31A-ALK and NPM1-ALK fusions. Haematologica. 2010;95:509–13.

    Article  Google Scholar 

  13. Janoueix-Lerosey I, Lequin D, Brugieres L, Ribeiro A, de Pontual L, Combaret V, et al. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature. 2008;455:967–70.

    Article  CAS  Google Scholar 

  14. Bonvini P, Zin A, Alaggio R, Pawel B, Bisogno G, Rosolen A. High ALK mRNA expression has a negative prognostic significance in rhabdomyosarcoma. Br J Cancer. 2013;109:3084–91.

    Article  CAS  Google Scholar 

  15. Ishibashi Y, Miyoshi H, Hiraoka K, Arakawa F, Haraguchi T, Nakashima S, et al. Anaplastic lymphoma kinase protein expression, genetic abnormalities, and phosphorylation in soft tissue tumors: Phosphorylation is associated with recurrent metastasis. Oncol Rep. 2015;33:1667–74.

    Article  CAS  Google Scholar 

  16. Kimbara S, Takeda K, Fukushima H, Inoue T, Okada H, Shibata Y, et al. A case report of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion gene treated with the ALK inhibitor, crizotinib. Jpn J Clin Oncol. 2014;44:868–71.

    Article  Google Scholar 

  17. Jiang Q, Tong HX, Hou YY, Zhang Y, Li JL, Zhou YH, et al. Identification of EML4-ALK as an alternative fusion gene in epithelioid inflammatory myofibroblastic sarcoma. Orphanet J Rare Dis. 2017;12:97.

    Article  Google Scholar 

  18. Mansfield AS, Murphy SJ, Harris FR, Robinson SI, Marks RS, Johnson SH, et al. Chromoplectic TPM3-ALK rearrangement in a patient with inflammatory myofibroblastic tumor who responded to ceritinib after progression on crizotinib. Ann Oncol. 2016;27:2111–7.

    Article  CAS  Google Scholar 

  19. Subbiah V, McMahon C, Patel S, Zinner R, Silva EG, Elvin JA, et al. STUMP un“stumped”: anti-tumor response to anaplastic lymphoma kinase (ALK) inhibitor based targeted therapy in uterine inflammatory myofibroblastic tumor with myxoid features harboring DCTN1-ALK fusion. J Hematol Oncol. 2015;8:66.

    Article  Google Scholar 

  20. Lee JC, Li CF, Huang HY, Zhu MJ, Marino-Enriquez A, Lee CT, et al. ALK oncoproteins in atypical inflammatory myofibroblastic tumours: novel RRBP1-ALK fusions in epithelioid inflammatory myofibroblastic sarcoma. J Pathol. 2017;241:316–23.

    Article  CAS  Google Scholar 

  21. Wiesner T, Lee W, Obenauf AC, Ran L, Murali R, Zhang QF, et al. Alternative transcription initiation leads to expression of a novel ALK isoform in cancer. Nature. 2015;526:453–7.

    Article  CAS  Google Scholar 

  22. Busam KJ, Vilain RE, Lum T, Busam JA, Hollmann TJ, Saw RP, et al. Primary and metastatic cutaneous melanomas express ALK through alternative transcriptional initiation. Am J Surg Pathol. 2016;40:786–95.

    Article  Google Scholar 

  23. Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med. 2011;17:313–9.

    Article  CAS  Google Scholar 

  24. Beck B, Blanpain C. Unravelling cancer stem cell potential. Nat Rev Cancer. 2013;13:727–38.

    Article  CAS  Google Scholar 

  25. Deshmukh A, Deshpande K, Arfuso F, Newsholme P, Dharmarajan A. Cancer stem cell metabolism: a potential target for cancer therapy. Mol Cancer. 2016;15:69.

    Article  Google Scholar 

  26. Xie X, Ye Z, Yang D, Tao H. Effects of combined c-myc and Bmi-1 siRNAs on the growth and chemosensitivity of MG-63 osteosarcoma cells. Mol Med Rep. 2013;8:168–72.

    Article  CAS  Google Scholar 

  27. Gravina GL, Festuccia C, Popov VM, Di Rocco A, Colapietro A, Sanita P, et al. c-Myc sustains transformed phenotype and promotes radioresistance of embryonal rhabdomyosarcoma cell lines. Radiat Res. 2016;185:411–22.

    Article  CAS  Google Scholar 

  28. Schulte JH, Bachmann HS, Brockmeyer B, Depreter K, Oberthur A, Ackermann S, et al. High ALK receptor tyrosine kinase expression supersedes ALK mutation as a determining factor of an unfavorable phenotype in primary neuroblastoma. Clin Cancer Res. 2011;17:5082–92.

    Article  CAS  Google Scholar 

  29. Zhou JX, Yang H, Deng Q, Gu X, He P, Lin Y, et al. Oncogenic driver mutations in patients with non-small-cell lung cancer at various clinical stages. Ann Oncol. 2013;24:1319–25.

    Article  CAS  Google Scholar 

  30. Todaro M, Francipane MG, Medema JP, Stassi G. Colon cancer stem cells: promise of targeted therapy. Gastroenterology. 2010;138:2151–62.

    Article  CAS  Google Scholar 

  31. Dandawate PR, Subramaniam D, Jensen RA, Anant S. Targeting cancer stem cells and signaling pathways by phytochemicals: novel approach for breast cancer therapy. Semin Cancer Biol. 2016;40-41:192–208.

    Article  CAS  Google Scholar 

  32. Brown HK, Tellez-Gabriel M, Heymann D. Cancer stem cells in osteosarcoma. Cancer Lett. 2017;386:189–95.

    Article  CAS  Google Scholar 

  33. Fujiwara T, Ozaki T. Overcoming therapeutic resistance of bone sarcomas: overview of the molecular mechanisms and therapeutic targets for bone sarcoma stem cells. Stem Cells Int. 2016;2016:2603092.

    Article  Google Scholar 

  34. Kuo CY, Ann DK. When fats commit crimes: fatty acid metabolism, cancer stemness and therapeutic resistance. Cancer Commun (Lond). 2018;38:47.

    Article  Google Scholar 

  35. Riggi N, Cironi L, Provero P, Suva ML, Kaloulis K, Garcia-Echeverria C, et al. Development of Ewing’s sarcoma from primary bone marrow-derived mesenchymal progenitor cells. Cancer Res. 2005;65:11459–68.

    Article  CAS  Google Scholar 

  36. Haldar M, Hancock JD, Coffin CM, Lessnick SL, Capecchi MR. A conditional mouse model of synovial sarcoma: insights into a myogenic origin. Cancer Cell. 2007;11:375–88.

    Article  CAS  Google Scholar 

  37. Feng BH, Liu AG, Gu WG, Deng L, Cheng XG, Tong TJ, et al. CD133+ subpopulation of the HT1080 human fibrosarcoma cell line exhibits cancer stem-like characteristics. Oncol Rep. 2013;30:815–23.

    Article  CAS  Google Scholar 

  38. Huang FF, Wu DS, Zhang L, Yu YH, Yuan XY, Li WJ, et al. Inactivation of PTEN increases ABCG2 expression and the side population through the PI3K/Akt pathway in adult acute leukemia. Cancer Lett. 2013;336:96–105.

    Article  CAS  Google Scholar 

  39. Xia P, Xu XY. PI3K/Akt/mTOR signaling pathway in cancer stem cells: from basic research to clinical application. Am J Cancer Res. 2015;5:1602–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Kim J, Woo AJ, Chu J, Snow JW, Fujiwara Y, Kim CG, et al. A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell. 2010;143:313–24.

    Article  CAS  Google Scholar 

  41. Lin CY, Loven J, Rahl PB, Paranal RM, Burge CB, Bradner JE, et al. Transcriptional amplification in tumor cells with elevated c-Myc. Cell. 2012;151:56–67.

    Article  CAS  Google Scholar 

  42. Wang Y, Cheng J, Xie D, Ding X, Hou H, Chen X, et al. NS1-binding protein radiosensitizes esophageal squamous cell carcinoma by transcriptionally suppressing c-Myc. Cancer Commun (Lond). 2018;38:33.

    Article  Google Scholar 

  43. Porro A, Iraci N, Soverini S, Diolaiti D, Gherardi S, Terragna C, et al. c-MYC oncoprotein dictates transcriptional profiles of ATP-binding cassette transporter genes in chronic myelogenous leukemia CD34+ hematopoietic progenitor cells. Mol Cancer Res. 2011;9:1054–66.

    Article  CAS  Google Scholar 

  44. Porro A, Haber M, Diolaiti D, Iraci N, Henderson M, Gherardi S, et al. Direct and coordinate regulation of ATP-binding cassette transporter genes by Myc factors generates specific transcription signatures that significantly affect the chemoresistance phenotype of cancer cells. J Biol Chem. 2010;285:19532–43.

    Article  CAS  Google Scholar 

Download references


This work was supported by the National Key Research and Development Program (2017YFA0505600) and the National Natural Science Foundation of China Programs (Grant Nos 81772863 and 81572403). We thank Dr Deng Xianming (Principal Investigator for Chemical Biology and Medicinal Chemistry School of Life Sciences, Xiamen University, China) for generously providing the plasmids.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Xing Zhang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

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

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, BS., Chen, HY., Que, Y. et al. ALKATI interacts with c-Myc and promotes cancer stem cell-like properties in sarcoma. Oncogene 39, 151–163 (2020).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links