Page 28 - Haematologica-April 2018

R. Marke et al.
Figure 5. IKZF1 alterations mediate therapy resistance. Overview of IKZF1-affected pathways contributing to tyrosine kinase inhibitor (TKI) resistance and glucocor- ticoid (GC) resistance. Enhanced cell adhesion due to loss of IKZF1 function has been shown to contribute to both TKI and GC resistance. Deregulation of metabolic pathways, such as LKB1/AMPK signaling and glucose metabolism, attenuated glucocorticoid receptor (GR) target gene regulation and upregulation of epithelial membrane protein 1 (EMP1) have been implicated in mediating GC resistance of IKZF1-deleted BCP-ALL. Green boxes indicate activated targets or pathways, while red boxes define attenuated pathways. Targets within the metabolic pathway can either promote or inhibit GC resistance.
ALL. However, more recently the role of IKZF1 deletions steroid pulses during maintenance therapy,81 may already as an independent prognostic marker has been prevent relapses. For the near future, more systematic challenged,119 as has the specific contributions of whole screens aimed at determining specific vulnerabilities of
572
gene versus intragenic dominant-negative IKZF1 deletions.86 One potential explanation for such disparities may relate to differences in scheduling and dosing of spe- cific therapeutic agents between different treatment pro- tocols. It will, therefore, be important to study these pro- tocol-dependent differences in order to define what is cur- rently the most efficient treatment for IKZF1-deleted ALL. Certain adjustments, such as the addition of vincristine-
IKZF1-deleted ALL may lead to the identification of tar- geted therapies that can re-sensitize this high-risk ALL subgroup to curative treatment.
Acknowledgments
This work was supported by Stichting Kinderen Kankervrij (KiKa; grant numbers KiKa 2009-55 and KiKa 2010-77) and Stichting KOC Nijmegen.
References
1. Hunger SP, Mullighan CG. Acute lym- phoblastic Leukemia in children. N Engl J Med. 2015;373(16):1541-1552.
2. Iacobucci I, Mullighan CG. Genetic Basis of Acute Lymphoblastic Leukemia. J Clin Oncol. 2017;35(9):975-983.
3. Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lym- phoblastic leukemia. N Engl J Med. 2009;360(5):470-480.
4. Kuiper RP, Waanders E, van der Velden VH, et al. IKZF1 deletions predict relapse in uni- formly treated pediatric precursor B-ALL. Leukemia. 2010;24(7):1258-1264.
5. John LB, Ward AC. The Ikaros gene family: transcriptional regulators of hematopoiesis and immunity. Mol Immunol. 2011;48(9- 10):1272-1278.
6. Yoshida T, Georgopoulos K. Ikaros fingers on lymphocyte differentiation. Int J Hematol. 2014;100(3):220-229.
7. Kim J, Sif S, Jones B, et al. Ikaros DNA-bind- ing proteins direct formation of chromatin remodeling complexes in lymphocytes. Immunity. 1999;10(3):345-355.
8. Koipally J, Renold A, Kim J, Georgopoulos K. Repression by Ikaros and Aiolos is medi- ated through histone deacetylase complex- es. EMBO J. 1999;18(11):3090-3100.
9. Sridharan R, Smale ST. Predominant interac- tion of both Ikaros and Helios with the NuRD complex in immature thymocytes. J Biol Chem. 2007;282(41):30227-30238.
10. Liang Z, Brown KE, Carroll T, et al. A high- resolution map of transcriptional repression. Elife. 2017;6.
11. Zhang J, Jackson AF, Naito T, et al. Harnessing of the nucleosome-remodeling- deacetylase complex controls lymphocyte development and prevents leukemogenesis. Nat Immunol. 2011;13(1):86-94.
12. Schwickert TA, Tagoh H, Gultekin S, et al. Stage-specific control of early B cell develop- ment by the transcription factor Ikaros. Nat Immunol. 2014;15(3):283-293.
13. Ross J, Mavoungou L, Bresnick EH, Milot E. GATA-1 utilizes Ikaros and polycomb repressive complex 2 to suppress Hes1 and to promote erythropoiesis. Mol Cell Biol. 2012;32(18):3624-3638.
14. Oravecz A, Apostolov A, Polak K, et al. Ikaros mediates gene silencing in T cells through Polycomb repressive complex 2. Nat Commun. 2015;6:8823.
15. Koipally J, Georgopoulos K. Ikaros interac- tions with CtBP reveal a repression mecha- nism that is independent of histone deacety- lase activity. J Biol Chem. 2000;275(26):19594-19602.
16. Koipally J, Georgopoulos K. Ikaros-CtIP interactions do not require C-terminal bind-
ing protein and participate in a deacetylase- independent mode of repression. J Biol Chem. 2002;277(26):23143-23149.
17. O'Neill DW, Schoetz SS, Lopez RA, et al. An ikaros-containing chromatin-remodeling complex in adult-type erythroid cells. Mol Cell Biol. 2000;20(20):7572-7582.
18. Bottardi S, Mavoungou L, Pak H, et al. The IKAROS interaction with a complex includ- ing chromatin remodeling and transcription elongation activities is required for hematopoiesis. PLoS Genet. 2014;10(12): e1004827.
19. Bottardi S, Zmiri FA, Bourgoin V, et al. Ikaros interacts with P-TEFb and cooperates with GATA-1 to enhance transcription elonga- tion. Nucleic Acids Res. 2011;39(9):3505- 3519.
20. Popescu M, Gurel Z, Ronni T, et al. Ikaros stability and pericentromeric localization are regulated by protein phosphatase 1. J Biol Chem. 2009;284(20):13869-13880.
21. Gowda C, Song C, Kapadia M, et al. Regulation of cellular proliferation in acute lymphoblastic leukemia by Casein Kinase II (CK2) and Ikaros. Adv Biol Regul. 2017;63:71-80.
22. Gomez-del Arco P, Maki K, Georgopoulos K. Phosphorylation controls Ikaros's ability to negatively regulate the G(1)-S transition. Mol Cell Biol. 2004;24(7):2797-2807.
23. Song C, Gowda C, Pan X, et al. Targeting
haematologica | 2018; 103(4)