Open Access

Identification and characterization of a murine model of BCR‑ABL1+ acute B‑lymphoblastic leukemia with central nervous system metastasis

  • Authors:
    • Xiaozhuo Yu
    • Hua Zhang
    • Meng Yuan
    • Ping Zhang
    • Yang Wang
    • Mingzhe Zheng
    • Zhuangwei Lv
    • Woodvine Otieno Odhiambo
    • Canyu Li
    • Chengcheng Liu
    • Yunfeng Ma
    • Yanhong Ji
  • View Affiliations

  • Published online on: June 3, 2019     https://doi.org/10.3892/or.2019.7184
  • Pages: 521-532
  • Copyright: © Yu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Breakpoint cluster region (BCR)‑Abelson murine leukemia (ABL)1+ acute B‑lymphoblastic leukemia (B‑ALL) is a disease associated with a dismal prognosis and a high incidence of central nervous system (CNS) metastasis. However, BCR‑ABL1+ B‑ALL with CNS infiltration has not been previously characterized, at least to the best of our knowledge. In the present study, a murine model of BCR‑ABL1+ B‑ALL with CNS metastasis was established using retroviral transduction. The vast majority of BCR‑ABL1+ leukemic cells were found to be immature B cells with a variable proportion of pro‑B and pre‑B populations. The present results indicated that the BCR‑ABL1+ B‑leukemic cells expressed high levels integrin subunit alpha 6 (Itga6) and L‑selectin adhesion molecules, and have an intrinsic ability to disseminate and accumulate in CNS tissues, predominantly in meninges. On the whole, these results provide an approach for addressing the mechanisms of BCR‑ABL1+ B‑ALL with CNS metastasis and may guide the development of novel therapeutic strategies.

References

1 

Bernt KM and Hunger SP: Current concepts in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia. Front Oncol. 4:542014. View Article : Google Scholar : PubMed/NCBI

2 

Quintás-Cardama A and Cortes J: Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood. 113:1619–1630. 2009. View Article : Google Scholar : PubMed/NCBI

3 

Schjerven H, Ayongaba EF, Aghajanirefah A, McLaughlin J, Cheng D, Geng H, Boyd JR, Eggesbø LM, Lindeman I, Heath JL, et al: Genetic analysis of Ikaros target genes and tumor suppressor function in BCR-ABL1+ pre-B ALL. J Exp Med. 214:793–814. 2017.PubMed/NCBI

4 

Pfeifer H, Wassmann B, Hofmann WK, Komor M, Scheuring U, Brück P, Binckebanck A, Schleyer E, Gökbuget N, Wolff T, et al: Risk and prognosis of central nervous system leukemia in patients with Philadelphia chromosome-positive acute leukemias treated with imatinib mesylate. Clin Cancer Res. 9:4674–4681. 2003.PubMed/NCBI

5 

Mullighan CG: The molecular genetic makeup of acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2012:389–396. 2012.PubMed/NCBI

6 

Hamdi A, Mawad R, Bassett R, di SA, Ferro R, Afrough A, Ram R, Dabaja B, Rondon G, Champlin R, et al: Central nervous system relapse in adults with acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 20:1767–1771. 2014. View Article : Google Scholar : PubMed/NCBI

7 

Trendowski M: The inherent metastasis of leukaemia and its exploitation by sonodynamic therapy. Crit Rev Oncol Hematol. 94:149–163. 2015. View Article : Google Scholar : PubMed/NCBI

8 

Jabbour E, Thomas D, Cortes J, Kantarjian HM and O'Brien S: Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: Current and emerging therapies. Cancer. 116:2290–2300. 2010.PubMed/NCBI

9 

Arbonés ML, Ord DC, Ley K, Ratech H, Maynard-Curry C, Otten G, Capon DJ and Tedder TF: Lymphocyte homing and leukocyte rolling and migration are impaired in L-selectin-deficient mice. Immunity. 1:247–260. 1994. View Article : Google Scholar : PubMed/NCBI

10 

Campbell JJ, Hedrick J, Zlotnik A, Siani MA, Thompson DA and Butcher EC: Chemokines and the arrest of lymphocytes rolling under flow conditions. Science. 279:381–384. 1998. View Article : Google Scholar : PubMed/NCBI

11 

Ley K, Laudanna C, Cybulsky MI and Nourshargh S: Getting to the site of inflammation: The leukocyte adhesion cascade updated. Nat Rev Immunol. 7:678–689. 2007. View Article : Google Scholar : PubMed/NCBI

12 

Nourshargh S, Hordijk PL and Sixt M: Breaching multiple barriers: Leukocyte motility through venular walls and the interstitium. Nat Rev Mol Cell Biol. 11:366–378. 2010. View Article : Google Scholar : PubMed/NCBI

13 

Yao H, Price TT, Cantelli G, Ngo B, Warner MJ, Olivere L, Ridge SM, Jablonski EM, Therrien J, Tannheimer S, et al: Leukaemia hijacks a neural mechanism to invade the central nervous system. Nature. 560:55–60. 2018. View Article : Google Scholar : PubMed/NCBI

14 

Peng C and Li S: CML mouse model in translational research. Methods Mol Biol. 602:253–266. 2010. View Article : Google Scholar : PubMed/NCBI

15 

Roumiantsev S, de Aos IE, Varticovski L, Ilaria RL and Van Etten RA: The src homology 2 domain of Bcr/Abl is required for efficient induction of chronic myeloid leukemia-like disease in mice but not for lymphoid leukemogenesis or activation of phosphatidylinositol 3-kinase. Blood. 97:4–13. 2001. View Article : Google Scholar : PubMed/NCBI

16 

Li S, Ilaria RL, Million RP Jr, Daley GQ and Van Etten RA: The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity. J Exp Med. 189:1399–1412. 1999. View Article : Google Scholar : PubMed/NCBI

17 

Maheras KJ and Gow A: Increased anesthesia time using 2,2,2-tribromoethanol-chloral hydrate with low impact on mouse psychoacoustics. J Neurosci Method. 219:61–69. 2013. View Article : Google Scholar

18 

Anderson KG, Mayer-Barber K, Sung H, Beura L, James BR, Taylor JJ, Qunaj L, Griffith TS, Vezys V, Barber DL and Masopust D: Intravascular staining for discrimination of vascular and tissue leukocytes. Nat Protoc. 9:209–222. 2014. View Article : Google Scholar : PubMed/NCBI

19 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

20 

Krause DS, Katherine L, Lewis JB, Andrian UH and Van Etten RA: Selectins and their ligands are required for homing and engraftment of BCR-ABL1+ leukemic stem cells in the bone marrow niche. Blood. 123:1361–1371. 2014. View Article : Google Scholar : PubMed/NCBI

21 

Levinsen M, Taskinen M, Abrahamsson J, Forestier E, Frandsen TL, Harila-Saari A, Heyman M, Jonsson OG, Lähteenmäki PM, Lausen B, et al: Clinical features and early treatment response of central nervous system involvement in childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 61:1416–1421. 2014. View Article : Google Scholar : PubMed/NCBI

22 

Camicia R, Winkler HC and Hassa PO: Novel drug targets for personalized precision medicine in relapsed/refractory diffuse large B-cell lymphoma: A comprehensive review. Mol Cancer. 14:2072015. View Article : Google Scholar : PubMed/NCBI

23 

Krause S, Pfeiffer C, Strube S, Alsadeq A, Fedders H, Vokuhl C, Loges S, Waizenegger J, Ben-Batalla I, Cario G, et al: Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS). Blood. 125:820–830. 2015. View Article : Google Scholar : PubMed/NCBI

24 

Buchner M, Swaminathan S, Chen Z and Müschen M: Mechanisms of pre-B-cell receptor checkpoint control and its oncogenic subversion in acute lymphoblastic leukemia. Immunol Rev. 263:192–209. 2015. View Article : Google Scholar : PubMed/NCBI

25 

Score J, Calasanz MJ, Ottman O, Pane F, Yeh RF, Sobrinho-Simões MA, Kreil S, Ward D, Hidalgo-Curtis C, Melo JV, et al: Analysis of genomic breakpoints in p190 and p210 BCR-ABL indicate distinct mechanisms of formation. Leukemia. 24:1742–1750. 2010. View Article : Google Scholar : PubMed/NCBI

26 

Gu S, Sayad A, Chan G, Yang W, Lu Z, Virtanen C, Van Etten RA and Neel BG: SHP2 is required for BCR-ABL1-induced hematologic neoplasia. Leukemia. 32:203–213. 2018. View Article : Google Scholar : PubMed/NCBI

27 

Dong Y, Liu F, Wu C, Li S, Zhao X, Zhang P, Jiao J, Yu X, Ji Y and Zhang M: Illegitimate RAG-mediated recombination events are involved in IKZF1 Δ3–6 deletion in BCR-ABL1 lymphoblastic leukaemia. Clin Exp Immunol. 185:320–331. 2016. View Article : Google Scholar : PubMed/NCBI

28 

Morotti A, Panuzzo C, Crivellaro S, Pergolizzi B, Familiari U, Berger AH, Saglio G and Pandolfi PP: BCR-ABL disrupts PTEN nuclear-cytoplasmic shuttling through phosphorylation-dependent activation of HAUSP. Leukemia. 28:1326–1333. 2014. View Article : Google Scholar : PubMed/NCBI

29 

Dash AB, Williams IR, Kutok JL, Tomasson MH, Anastasiadou E, Lindahl K, Li S, Van Etten RA, Borrow J, Housman D, et al: A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9. Proc Natl Acad Sci USA. 99:7622–7627. 2002. View Article : Google Scholar : PubMed/NCBI

30 

Zhang H, Peng C, Hu Y, Li H, Sheng Z, Chen Y, Sullivan C, Cerny J, Hutchinson L, Higgins A, et al: The Blk pathway functions as a tumor suppressor in chronic myeloid leukemia stem cells. Nat Genet. 44:861–871. 2012. View Article : Google Scholar : PubMed/NCBI

31 

Vegh P, Winckler J and Melchers F: Long-term ‘in vitro’ proliferating mouse hematopoietic progenitor cell lines. Immunol Lett. 130:32–35. 2010. View Article : Google Scholar : PubMed/NCBI

32 

Holl TM, Haynes BF and Kelsoe G: Stromal cell independent B cell development in vitro: Generation and recovery of autoreactive clones. J Immunol Methods. 354:53–67. 2010. View Article : Google Scholar : PubMed/NCBI

33 

Ji Y, Resch W, Corbett E, Yamane A, Casellas R and Schatz DG: The in vivo pattern of binding of RAG1 and RAG2 to antigen receptor loci. Cell. 141:419–431. 2010. View Article : Google Scholar : PubMed/NCBI

34 

Dong Y, Wu C, Zhao X, Zhang P, Zhang H, Zheng M, Li S, Jiao J, Yu X, Lv Z and Ji Y: Epigenetic modifications of the VH region after DJH recombination in Pro-B cells. Immunology. 152:218–231. 2017. View Article : Google Scholar : PubMed/NCBI

35 

Hardy RR and Hayakawa K: B cell development pathways. Annu Rev Immunol. 19:595–621. 2001. View Article : Google Scholar : PubMed/NCBI

36 

Wu C, Dong Y, Zhao X, Zhang P, Zheng M, Zhang H, Li S, Jin Y, Ma Y, Ren H and Ji Y: RAG2 involves the Igκ locus demethylation during B cell development. Mol Immunol. 88:125–134. 2017. View Article : Google Scholar : PubMed/NCBI

37 

Pippard MJ, Callender ST and Sheldon PW: Infiltration of central nervous system in adult acute myeloid leukaemia. Br Med J. 1:227–229. 1979. View Article : Google Scholar : PubMed/NCBI

38 

Prieto C, López-Millán B, Roca-Ho H, Stam RW, Romero-Moya D, Rodríguez-Baena FJ, Sanjuan-Pla A, Ayllón V, Ramírez M, Bardini M, et al: NG2 antigen is involved in leukemia invasiveness and central nervous system infiltration in MLL-rearranged infant B-ALL. Leukemia. 32:633–644. 2018. View Article : Google Scholar : PubMed/NCBI

39 

Roddie P, Collie D and Johnson P: Myelomatous involvement of the dura mater: A rare complication of multiple myeloma. J Clin Pathol. 53:398–399. 2000. View Article : Google Scholar : PubMed/NCBI

40 

Cheung LC, Tickner J, Hughes AM, Skut P, Howlett M, Foley B, Oommen J, Wells JE, He B, Singh S, et al: New therapeutic opportunities from dissecting the pre-B leukemia bone marrow microenvironment. Leukemia. 32:2326–2338. 2018. View Article : Google Scholar : PubMed/NCBI

41 

Colognato H, ffrench-Constant C and Feltri ML: Human diseases reveal novel roles for neural laminins. Trends Neurosci. 28:480–486. 2005. View Article : Google Scholar : PubMed/NCBI

42 

Wang L, Dong Z, Zhang Y and Miao J: The roles of integrin β4 in vascular endothelial cells. J Cell Physiol. 227:474–478. 2012. View Article : Google Scholar : PubMed/NCBI

43 

Salomão DR, Pulido JS, Johnston PB, Canal-Fontcuberta I and Feldman AL: Vitreoretinal presentation of secondary large B-cell lymphoma in patients with systemic lymphoma. JAMA Ophthalmol. 131:1151–1158. 2013. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

August 2019
Volume 42 Issue 2

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Yu, X., Zhang, H., Yuan, M., Zhang, P., Wang, Y., Zheng, M. ... Ji, Y. (2019). Identification and characterization of a murine model of BCR‑ABL1+ acute B‑lymphoblastic leukemia with central nervous system metastasis. Oncology Reports, 42, 521-532. https://doi.org/10.3892/or.2019.7184
MLA
Yu, X., Zhang, H., Yuan, M., Zhang, P., Wang, Y., Zheng, M., Lv, Z., Odhiambo, W. O., Li, C., Liu, C., Ma, Y., Ji, Y."Identification and characterization of a murine model of BCR‑ABL1+ acute B‑lymphoblastic leukemia with central nervous system metastasis". Oncology Reports 42.2 (2019): 521-532.
Chicago
Yu, X., Zhang, H., Yuan, M., Zhang, P., Wang, Y., Zheng, M., Lv, Z., Odhiambo, W. O., Li, C., Liu, C., Ma, Y., Ji, Y."Identification and characterization of a murine model of BCR‑ABL1+ acute B‑lymphoblastic leukemia with central nervous system metastasis". Oncology Reports 42, no. 2 (2019): 521-532. https://doi.org/10.3892/or.2019.7184