Ann Transl Med. 2016 Oct;4(19):363. doi: 10.21037/atm.2016.09.29.

Variations in mRNA and protein levels of Ikaros family members in pediatric T cell acute lymphoblastic leukemia.

Annals of translational medicine

Julie L Mitchell, Thomas M Yankee

PMID: 27826566 PMCID: PMC5075847 DOI: 10.21037/atm.2016.09.29

Abstract

BACKGROUND: Pediatric T cell acute lymphoblastic leukemia (T-ALL) is a highly heterogeneous disease in which the cells share phenotypic characteristics with normal human thymocytes. The Ikaros family of transcription factors includes five members that are required for normal T cell development and are implicated in leukemogenesis. The goal of this work was to correlate the pattern of expression of Ikaros family members with the phenotype of the T-ALL cells.

METHODS: We obtained twenty-four samples from pediatric T-ALL patients and used multi-parameter flow cytometry to characterize each sample, comparing the phenotype of the leukemic cells with normal human thymocytes. Then, we defined the expression levels of each Ikaros family member to determine whether the mRNA levels or splicing or protein levels were similar to the normal patterns seen during human T cell development.

RESULTS: Multi-parameter analysis of the phenotype of T-ALL cells revealed that each patient's cells were unique and could not be readily correlated with stages of T cell development. Similarly, the pattern of Ikaros expression varied among patients. In most patients, Ikaros mRNA was the dominant family member expressed, but some patients' cells contained mostly Helios, Aiolos, or Eos mRNA. Despite that most patients had elevated mRNA levels of Ikaros family members and unique patterns of mRNA splicing, most patients had significantly reduced protein levels of Ikaros and Aiolos.

CONCLUSIONS: Our analysis of the cell phenotype and Ikaros expression levels in T-ALL cells revealed the extent of heterogeneity among patients. While it is rarely possible to trace leukemic cells to their developmental origin, we found distinct patterns of Ikaros family mRNA levels in groups of patients. Further, mRNA and protein levels of Ikaros and Aiolos did not correlate, indicating that mRNA and protein levels are regulated via distinct mechanisms.

Keywords: Aiolos; Helios; Ikaros; pediatric T cell acute lymphoblastic leukemia (pediatric T-ALL)

Conflict of interest statement

References

1. FEBS Lett. 2007 Apr 17;581(8):1605-16 - PubMed
2. Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):244-9 - PubMed
3. Leukemia. 2007 Jun;21(6):1258-66 - PubMed
4. J Immunol. 2008 Nov 1;181(9):6265-74 - PubMed
5. Stem Cells. 2001;19(3):165-79 - PubMed
6. J Immunol. 2005 Sep 15;175(6):3508-15 - PubMed
7. Cell Immunol. 1993 Oct 15;151(2):481-90 - PubMed
8. Cancer Cell. 2002 Feb;1(1):75-87 - PubMed
9. Genes Dev. 1998 Mar 15;12(6):782-96 - PubMed
10. Science. 2004 Oct 8;306(5694):269-71 - PubMed
11. Clin Exp Immunol. 1990 Sep;81(3):466-74 - PubMed
12. Sci Signal. 2014 Mar 18;7(317):ra28 - PubMed
13. Immunology. 1989 Apr;66(4):517-25 - PubMed
14. Cancer Res. 2000 Aug 1;60(15):4062-5 - PubMed
15. J Immunol. 1995 Aug 15;155(4):1862-72 - PubMed
16. Br J Haematol. 2004 Apr;125(1):31-7 - PubMed
17. Blood. 2003 Apr 1;101(7):2693-703 - PubMed
18. Blood. 2007 Mar 1;109(5):2190-7 - PubMed
19. J Immunol. 1990 Jan 1;144(1):66-74 - PubMed
20. PLoS One. 2013 Aug 15;8(8):e72326 - PubMed
21. Nature. 2008 May 1;453(7191):110-4 - PubMed
22. Br J Haematol. 2009 Jan;144(2):268-70 - PubMed
23. Immunity. 2003 Jul;19(1):131-44 - PubMed
24. Immunol Res. 2016 Apr;64(2):565-75 - PubMed
25. Blood. 2003 Oct 1;102(7):2444-51 - PubMed
26. Mol Cell Biol. 2008 Dec;28(24):7465-75 - PubMed
27. Blood. 1993 Aug 1;82(3):889-94 - PubMed
28. EMBO J. 1990 Oct;9(10):3343-51 - PubMed
29. J Clin Oncol. 1999 Dec;17(12):3753-66 - PubMed
30. Blood. 2013 Mar 7;121(10):1769-82 - PubMed
31. Leukemia. 2008 Jan;22(1):124-31 - PubMed
32. PLoS One. 2015 Jul 01;10(7):e0130756 - PubMed
33. Cell. 1995 Oct 20;83(2):289-99 - PubMed
34. Blood. 2008 Feb 1;111(3):1396-403 - PubMed
35. J Exp Med. 2005 Jun 6;201(11):1715-23 - PubMed
36. Leukemia. 1995 Oct;9(10):1783-6 - PubMed
37. Nat Immunol. 2013 Oct;14(10):1073-83 - PubMed
38. Blood. 2009 Mar 26;113(13):2988-98 - PubMed
39. Pediatr Blood Cancer. 2008 Dec;51(6):737-40 - PubMed
40. J Egypt Natl Canc Inst. 2008 Jun;20(2):111-20 - PubMed
41. Blood. 2009 Apr 2;113(14):3254-63 - PubMed
42. Curr Biol. 1998 Apr 23;8(9):508-15 - PubMed
43. Blood. 2013 Oct 31;122(18):3149-59 - PubMed
44. Nat Med. 2012 Feb 26;18(3):436-40 - PubMed
45. Blood. 1999 Nov 15;94(10):3491-8 - PubMed
46. Oncogene. 2006 Feb 16;25(7):1118-24 - PubMed
47. Blood. 2014 Dec 4;124(24):3577-82 - PubMed
48. Blood. 2009 Jul 30;114(5):972-82 - PubMed
49. Mol Cell Biol. 1994 Dec;14(12):8292-303 - PubMed
50. Blood. 2005 Apr 15;105(8):3072-8 - PubMed
51. Nature. 2007 Jun 21;447(7147):966-71 - PubMed
52. Eur J Immunol. 1992 Nov;22(11):3033-6 - PubMed
53. EMBO J. 1996 Oct 1;15(19):5358-69 - PubMed
54. Blood Cells Mol Dis. 2008 Nov-Dec;41(3):278-83 - PubMed
55. J Biol Chem. 2000 Dec 8;275(49):38347-54 - PubMed
56. Cancer Cell. 2003 Jun;3(6):551-64 - PubMed
57. J Immunol. 2008 Nov 15;181(10):6820-8 - PubMed
58. Leuk Res. 2010 Apr;34(4):426-9 - PubMed
59. Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):680-5 - PubMed
60. Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18261-6 - PubMed
61. Immunity. 1996 Dec;5(6):537-49 - PubMed
62. Eur J Immunol. 2002 Mar;32(3):720-30 - PubMed
63. EMBO J. 1997 Apr 15;16(8):2004-13 - PubMed
64. Haematologica. 2011 Dec;96(12):1874-7 - PubMed
65. J Biol Chem. 2008 Apr 18;283(16):10476-84 - PubMed
66. Clin Cancer Res. 1999 Aug;5(8):2112-20 - PubMed
67. Immunity. 1998 Oct;9(4):543-53 - PubMed

Publication Types

• Journal Article

Grant support

• P30 GM103326/GM/NIGMS NIH HHS/United States
• U10 CA098543/CA/NCI NIH HHS/United States
• U24 CA114766/CA/NCI NIH HHS/United States