Skip to main content

Advertisement

SpringerLink
Log in

Copy number abnormality of acute lymphoblastic leukemia cell lines based on their genetic subtypes

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

In this study, we performed genetic analysis of 83 B cell precursor acute lymphoblastic leukemia (B-ALL) cell lines. First, we performed multiplex ligation-dependent probe amplification analysis to identify copy number abnormalities (CNAs) in eight genes associated with B-ALL according to genetic subtype. In Ph+ B-ALL cell lines, the frequencies of IKZF1, CDKN2A/2B, BTG1, and PAX5 deletion were significantly higher than those in Ph− B-ALL cell lines. The frequency of CDKN2A/2B deletion in KMT2A rearranged cell lines was significantly lower than that in non-KMT2A rearranged cell lines. These findings suggest that CNAs are correlated with genetic subtype in B-ALL cell lines. In addition, we determined that three B-other ALL cell lines had IKZF1 deletions (YCUB-5, KOPN49, and KOPN75); we therefore performed comprehensive genetic analysis of these cell lines. YCUB-5, KOPN49, and KOPN75 had P2RY8-CRLF2, IgH-CRLF2, and PAX5-ETV6 fusions, respectively. Moreover, targeted capture sequencing revealed that YCUB-5 had JAK2 R683I and KRAS G12D, and KOPN49 had JAK2 R683G and KRAS G13D mutations. These data may contribute to progress in the field of leukemia research.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

References

  1. Liem NL, Papa RA, Milross CG, Schmid MA, Tajbakhsh M, Choi S, et al. Characterization of childhood acute lymphoblastic leukemia xenograft models for the preclinical evaluation of new therapies. Blood. 2004;103(10):3905–14.

    Article  PubMed  CAS  Google Scholar 

  2. McCormack E, Bruserud O, Gjertsen BT. Animal models of acute myelogenous leukaemia—development, application and future perspectives. Leukemia. 2005;19(5):687–706.

    Article  PubMed  CAS  Google Scholar 

  3. Maude SL, Tasian SK, Vincent T, Hall JW, Sheen C, Roberts KG, et al. Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia. Blood. 2012;120(17):3510–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Den Boer ML, van Slegtenhorst M, De Menezes RX, Cheok MH, Buijs-Gladdines JG, Peters ST, et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol. 2009;10(2):125–34.

    Article  CAS  Google Scholar 

  5. Roberts KG, Li Y, Payne-Turner D, Harvey RC, Yang YL, Pei D, McCastlain K, et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. New Engl J of Med. 2014;371:1005–15.

    Article  CAS  Google Scholar 

  6. Hirose M, Minato K, Tobinai K, Ohira M, Ise T, Watanabe S, Shimoyama M, Taniwaki M, Abe T. A novel pre-T cell line derived from acute lymphoblastic leukemia. Gan. 1982;73(4):600–5.

    PubMed  CAS  Google Scholar 

  7. Minegishi M, Tsuchiya S, Minegishi N, Konno T. Establishment of five human malignant non-T lymphoid cell lines and mixed lymphocyte-tumor reaction. Tohoku J Exp Med. 1987;151:283–92.

    Article  PubMed  CAS  Google Scholar 

  8. Kawamura M, Kikuchi A, Kobayashi S, Hanada R, Yamamoto K, Horibe K, et al. Mutations of the p53 and ras genes in childhood t(1;19)-acute lymphoblastic leukemia. Blood. 1995;85(9):2546–52.

    PubMed  CAS  Google Scholar 

  9. Ariyasu T, Matsuo Y, Harashima A, Nakamura S, Takaba S, Tsubota T, et al. Establishment and characterization of “biphenotypic” acute leukemia cell lines with a variant Ph translocation t(9;22;10) (q34;q11;q22). Hum Cell. 1998;11(1):43–50.

    PubMed  CAS  Google Scholar 

  10. Kang J, Kisenge RR, Toyoda H, Tanaka S, Bu J, Azuma E, et al. Chemical sensitization and regulation of TRAIL-induced apoptosis in a panel of B-lymphocytic leukaemia cell lines. Br J Haematol. 2003;123:921–32.

    Article  PubMed  CAS  Google Scholar 

  11. Goto H, Naruto T, Tanoshima R, Kato H, Yokosuka T, Yanagimachi M, et al. Chemo-sensitivity in a panel of B-cell precursor acute lymphoblastic leukemia cell lines, YCUB series, derived from children. Leu Res. 2009;33:1386–91.

    Article  CAS  Google Scholar 

  12. Hirase C, Maeda Y, Takai S, Kanamaru A. Hypersensitivity of Ph-positive lymphoid cell lines to rapamycin: possible clinical application of mTOR inhibitor. Leuk Res. 2009;33:450–9.

    Article  PubMed  CAS  Google Scholar 

  13. Shiotsu Y, Kiyoi H, Ishikawa Y, Tanizaki R, Shimizu M, Umehara H, et al. KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation. Blood. 2009;114:1607–17.

    Article  PubMed  CAS  Google Scholar 

  14. Hirose K, Inukai T, Kikuchi J, Furukawa Y, Ikawa T, Kawamoto H, et al. Aberrant induction of LMO2 by the E2A-HLF chimeric transcription factor and its implication in leukemogenesis of B-precursor ALL with t(17;19). Blood 2010;116:962–70.

    Article  CAS  Google Scholar 

  15. Okabe S, Tauchi T, Ohyashiki K. Establishment of a new Philadelphia chromosome-positive acute lymphoblastic leukemia cell line (SK-9) with T315I mutation. Exp Hematol. 2010;38:765–72.

    Article  PubMed  CAS  Google Scholar 

  16. Akbari Moqadam F, Boer JM, Lange-Turenhout EA, Pieters R, den Boer ML. Altered expression of miR-24, miR-126 and miR-365 does not affect viability of childhood TCF3-rearranged leukemia cells. Leukemia. 2014;28(5):1008–14.

    Article  PubMed  CAS  Google Scholar 

  17. Asai D, Imamura T, Suenobu S, Saito A, Hasegawa D, Deguchi T, et al. IKZF1 deletion is associated with a poor outcome in pediatric B-cell precursor acute lymphoblastic leukemia in Japan. Cancer Med. 2013;2:412–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Roberts KG, Morin RD, Zhang J, Hirst M, Zhao Y, Su X, et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell. 2012;22(2):153–66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Ishida H, Kanamitsu K, Washio K, Muraoka M, Sakakibara K, Matsubara T, et al. Relapsed infant MLL-rearranged acute lymphoblastic leukemia with additional genetic alterations. Pediatr Blood Cancer. 2016;63(11):2059–60.

    Article  PubMed  Google Scholar 

  20. Schwab CJ, Chilton L, Morrison H, Jones L, Al-Shehhi H, Erhorn A, et al. Genes commonly deleted in childhood B-cell precursor acute lymphoblastic leukemia: association with cytogenetics and clinical features. Haematologica. 2013;98(7):1081–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Imamura T, Kiyokawa N, Kato M, Imai C, Okamoto Y, Yano M, et al. Characterization of pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia with kinase fusions in Japan. Blood Cancer J. 2016;6:e419.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Reshmi SC, Harvey RC, Roberts KG, Stonerock E, Smith A, Jenkins H, et al. Targetable kinase gene fusions in high-risk B-ALL: a study from the Children’s Oncology Group. Blood. 2017;129(25):3352–61.

    PubMed  PubMed Central  CAS  Google Scholar 

  23. Kim WY, Sharpless NE. The regulation of INK4/ARF in cancer and aging. Cell. 2006;127(2):265–75.

    Article  PubMed  CAS  Google Scholar 

  24. van Zutven LJ, van Drunen E, de Bont JM, Wattel MM, Den Boer ML, Pieters R, et al. CDKN2 deletions have no prognostic value in childhood precursor-B acute lymphoblastic leukaemia. Leukemia. 2005;19(7):1281–4.

    Article  PubMed  CAS  Google Scholar 

  25. Braun M, Pastorczak A, Fendler W, Madzio J, Tomasik B, Taha J, et al. Biallelic loss of CDKN2A is associated with poor response to treatment in pediatric acute lymphoblastic leukemia. Leuk Lymphoma. 2017;58(5):1162–71.

    Article  PubMed  CAS  Google Scholar 

  26. Churchman ML, Low J, Qu C, Paietta EM, Kasper LH, Chang Y, et al. Efficacy of retinoids in IKZF1-mutated BCR-ABL1 acute lymphoblastic leukemia. Cancer Cell. 2015;28(3):343–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Rouault JP, Rimokh R, Tessa C, Paranhos G, Ffrench M, Duret L, et al. BTG1, a member of a new family of antiproliferative genes. EMBO J. 1992;11(4):1663–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Scheijen B, Boer JM, Marke R, Tijchon E, van Ingen Schenau D, Waanders E, et al. Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients. Haematologica. 2017;102(3):541–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Cazzaniga G, Daniotti M, Tosi S, Giudici G, Aloisi A, Pogliani E, et al. The paired box domain gene PAX5 is fused to ETV6/TEL in an acute lymphoblastic leukemia case. Cancer Res. 2001;61(12):4666–70.

    PubMed  CAS  Google Scholar 

  30. Strehl S, König M, Dworzak MN, Kalwak K, Haas OA. PAX5/ETV6 fusion defines cytogenetic entity dic(9;12)(p13;p13). Leukemia. 2003;17(6):1121–3.

    Article  PubMed  CAS  Google Scholar 

  31. Fazio G, Cazzaniga V, Palmi C, Galbiati M, Giordan M, te Kronnie G, et al. PAX5/ETV6 alters the gene expression profile of precursor B cells with opposite dominant effect on endogenous PAX5. Leukemia. 2013;27(4):992–5.

    Article  PubMed  CAS  Google Scholar 

  32. Chen IM, Harvey RC, Mullighan CG, Gastier-Foster J, Wharton W, Kang H, et al. Outcome modeling with CRLF2, IKZF1, JAK, and minimal residual disease in pediatric acute lymphoblastic leukemia: a Children’s Oncology Group study. Blood. 2012;119(15):3512–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

SU-Ph2 was established at Kinki University School of Medicine, Osaka, and provided in 2010 (Dr. Y. Maeda). TCCY was established at Tochigi Cancer Center and provided in 2011 (Dr. Y. Sato). HALO1 and SK9 were established at Tokyo Medical University, Tokyo, and provided in 1997 (Dr. T. Look in Dana-Farber Cancer Institute, Boston, MA) and in 2012 (Dr. S. Okabe), respectively. Endokun was established at Iwate Medical University, Morioka, and provided in 1997 (Dr. M. Endo). Kasumi2 established at Hiroshima University, Hiroshima, and provided in 2010 (Dr. T. Inaba).

Author information

Authors and Affiliations

  1. Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan

    Chihiro Tomoyasu, Toshihiko Imamura, Toshihiro Tomii & Hajime Hosoi

  2. Department of Pediatrics, National Hospital Organization Maizuru Medical Center, Maizuru, Japan

    Chihiro Tomoyasu

  3. Department of Pediatrics, Kyoto City Hospital, Kyoto, Japan

    Mio Yano

  4. Department of Pediatrics, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan

    Daisuke Asai

  5. Division of Hemato-Oncology and Regenerative Medicine, Kanagawa Children’s Medical Center, Yokohama, Japan

    Hiroaki Goto

  6. Department of Pediatric Hematology/Oncology, Okayama University Hospital, Okayama, Japan

    Akira Shimada

  7. Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    Masashi Sanada

  8. Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan

    Shotaro Iwamoto

  9. Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Junko Takita

  10. Japanese Red Cross Fukushima Blood Center, Okuma, Japan

    Masayoshi Minegishi

  11. Department of Pediatrics, Yamanashi University, Kofu, Japan

    Takeshi Inukai & Kanji Sugita

Authors
  1. Chihiro Tomoyasu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshihiko Imamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Toshihiro Tomii
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mio Yano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daisuke Asai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroaki Goto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Akira Shimada
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masashi Sanada
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shotaro Iwamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Junko Takita
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Masayoshi Minegishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Takeshi Inukai
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kanji Sugita
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hajime Hosoi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toshihiko Imamura.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest. A summary of relevant information will be published with the manuscript.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 264 KB)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tomoyasu, C., Imamura, T., Tomii, T. et al. Copy number abnormality of acute lymphoblastic leukemia cell lines based on their genetic subtypes. Int J Hematol 108, 312–318 (2018). https://doi.org/10.1007/s12185-018-2474-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-018-2474-7

Keywords

Search

Navigation