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IKZF1 in leukemia and therapy response
Figure 4. Effector pathways downstream of IKZF1 involved in leukemia pathogenesis. Loss of IKZF1 function due to IKZF1 gene deletions and mutations affects multiple pathways, including pre-B-cell receptor signaling, cell adhesion and proliferation, metabolic pathways and signal transducers and cell surface receptors. IKZF1 affects the expression of defined key molecules within each of these pathways, as indicated in the boxes. Green boxes define targets that are upregulated upon loss of IKZF1 function, while red boxes represent repressed targets. SRC: sarcoma proto-oncogene tyrosine kinase; SYK: spleen tyrosine kinase; IGLL1: immunoglobulin lambda-like polypeptide 1; SLP65: B-cell linker; RHO: RHO family of GTPases ; CTNND1: catenin delta 1/p120 catenin; FAK: focal adhesion kinase; ITGA5: integrin subunit alpha 5; THY1: thymus cell antigen 1; CDK6: cyclin dependent kinase 6; CDKN1A: cyclin dependent kinase inhibitor 1A; BCL6: B-cell lym- phoma 6; CDKN2A: cyclin dependent kinase inhibitor 2A; c-MYC: cellular myelocytomatosis oncogene; GLUT1/3/6: glucose transporter 1/3/6; INSR: insuline recep- tor; HK2: hexokinase 2; HK3: hexokinase 3; AMPK: AMP-activated protein kinase; LKB1: liver kinase B1; G6PD: glucose-6-phosphate dehydrogenase; TXNIP: thiore- doxin interacting protein; NR3C1: nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor); CNR2: cannabinoid receptor 2; FLT3: FMS related tyro- sine kinase 3; CD34: hematopoietic progenitor cell antigen; c-KIT: KIT receptor tyrosine kinase; CD43: sialophorin; IL7R: interleukin 7 receptor.
cells to the bone marrow niche. Indeed, FAK inhibition re- sensitizes BCR-ABL1 leukemic cells to tyrosine kinase inhibitor therapy.109 Similar results are observed after treat- ment with retinoids, specifically retinoid X receptor ago- nists, which induce expression of wild-type IKZF1, but not IK6, thereby abrogating expression of stem cell and adhe- sion molecules.63 Although these studies have provided important clues about how IKZF1 deletions alter treatment response especially in the context of BCR-ABL1-positive ALL, alternative mechanisms of therapy resistance may exist besides protection through cell interactions within the bone marrow microenvironment.
Synthetic glucocorticoids, such as prednisolone, consti- tute essential drugs in the treatment of ALL patients and glucocorticoid resistance remains a substantial problem in the treatment of BCP-ALL. There is accumulating evi- dence that IKZF1 deletions mediate prednisolone resist- ance in vivo,114,115 but different mechanisms have been pro- posed. IKZF1 actively represses genes of the phos- phatidylinositol-3 kinase pathway, including PIK3CD and PIK3C2B.23 Disruption of IKZF1 function, and subsequent activation of the PI3K/AKT/mTOR pathway can promote glucocorticoid resistance.116,117 IKZF1 controls expression of several genes involved in glucose and energy supply.110 This metabolic program may alter the threshold for responses to glucocorticoids in BCP-ALL. Specifically, the glucocorticoid receptor NR3C1 was reported to be a target of IKZF1 in pre-B ALL cells, and downregulation of NR3C1 protein levels could be observed upon expression of IK6.110 However, studies performed in murine Ikzf1+/- B cells and human BCP-ALL cell lines with short hairpin- mediated IKZF1 knockdown have demonstrated that loss of IKZF1 function induces glucocorticoid resistance inde-
pendently of altered NR3C1 mRNA and protein expres- sion.114 Indeed, IKZF1 itself appears to regulate NR3C1- dependent gene transcription.114 The transcriptional regu- lator BTG1 has been identified as a modifier of IKZF1- mediated resistance to glucocorticoid therapy and the combined loss of BTG1 and IKZF1 leads to an even stronger inhibition of glucocorticoid-induced cell death.48 Finally, IKZF1 target gene EMP1,106 which itself represents a poor prognostic factor in pediatric ALL, was shown to regulate the response to prednisolone, but also, on the other hand, to affect normal leukemic cell viability and proliferation.118 Collectively, these findings demonstrate that IKZF1, through modulation of different signaling pathways and acting directly on glucocorticoid target genes, alters treatment response, thereby mediating thera- py resistance in BCP-ALL (Figure 5).
Conclusions and perspectives
From this review it becomes clear that loss of IKZF1 function affects a broad variety of biological pathways which may all contribute to leukemia development. Moreover, the recently established roles for IKZF1 in cell adhesion, metabolism and glucocorticoid-dependent tar- get gene regulation seem to be important determinants of therapy resistance. Preclinical studies are helping with the identification of molecular pathways that can be exploit- ed for targeted therapy of IKZF1-deleted BCP-ALL.
Over the past decade, a large series of studies conducted in both childhood and adult ALL have provided clear evi- dence that IKZF1 alterations predict adverse outcome in BCP-ALL, both in BCR-ABL1-positive and -negative B-
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