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• W2551657950 abstract "•IKZF1 (IKAROS) deletions and mutations are a hallmark of high risk B-progenitor ALL, and are associated with poor outcome.•Genetic alteration of IKZF1 result in loss of IKAROS activity, with acquisition of a hematopoietic stem cell-like phenotype, and induction of adhesion molecule expression and signaling.•Mislocalization of leukemic cells in the bone marrow hematopoietic niche is characteristic of IKZF1-mutated B-ALL.•IKZF1 alterations create a therapeutic vulnerability by upregulating rexinoid receptor expression that can be targeted with rexinoid agonists.•Rexinoid agonists and focal adhesion kinase inhibitors synergize with tyrosine kinase inhibitors in IKZF1-mutated ALL. Genetic alterations of IKZF1 encoding the lymphoid transcription factor IKAROS are a hallmark of high-risk B-progenitor acute lymphoblastic leukemia (ALL), such as BCR-ABL1-positive (Ph+) and Ph-like ALL, and are associated with poor outcome even in the era of contemporary chemotherapy incorporating tyrosine kinase inhibitors. Recent experimental mouse modeling of B-progenitor ALL has shown that IKZF1 alterations have multiple effects, including arresting differentiation, skewing lineage of leukemia from myeloid to lymphoid, and, in Ph+ leukemia, conferring resistance to tyrosine kinase inhibitor (TKI) therapy without abrogating ABL1 inhibition. These effects are in part mediated by acquisition of an aberrant hematopoietic stem cell-like program accompanied by induction of cell surface expression of stem cell and adhesion molecules that mediate extravascular invasion and residence in the niche and activation of integrin signaling pathways. These effects can be exploited therapeutically using several approaches. IKZF1 alterations also result in upregulation of RXRA that encodes part of the heterodimeric retinoic acid X receptor. Rexinoids, a synthetic class of retinoids that bind specifically to retinoid “X” receptors such as bexarotene potently reverse aberrant adhesion and niche mislocalization in vivo and induce differentiation and cell cycle arrest. Focal adhesion kinase inhibitors block the downstream integrin-mediated signaling, reverse adhesion, and niche mislocalization. Both agents act synergistically with TKIs to prolong survival of Ph+ ALL in mouse and human xenograft model, with long-term remission induced by focal adhesion kinase inhibitors. Therefore, these findings provide important new conceptual insights into the mechanisms by which IKZF1 alterations result in drug resistance and indicate that therapeutic strategies directed against the pathways deregulated by mutation, rather than attempting to restore IKZF1 expression directly, represent promising therapeutic approaches in this disease. Genetic alterations of IKZF1 encoding the lymphoid transcription factor IKAROS are a hallmark of high-risk B-progenitor acute lymphoblastic leukemia (ALL), such as BCR-ABL1-positive (Ph+) and Ph-like ALL, and are associated with poor outcome even in the era of contemporary chemotherapy incorporating tyrosine kinase inhibitors. Recent experimental mouse modeling of B-progenitor ALL has shown that IKZF1 alterations have multiple effects, including arresting differentiation, skewing lineage of leukemia from myeloid to lymphoid, and, in Ph+ leukemia, conferring resistance to tyrosine kinase inhibitor (TKI) therapy without abrogating ABL1 inhibition. These effects are in part mediated by acquisition of an aberrant hematopoietic stem cell-like program accompanied by induction of cell surface expression of stem cell and adhesion molecules that mediate extravascular invasion and residence in the niche and activation of integrin signaling pathways. These effects can be exploited therapeutically using several approaches. IKZF1 alterations also result in upregulation of RXRA that encodes part of the heterodimeric retinoic acid X receptor. Rexinoids, a synthetic class of retinoids that bind specifically to retinoid “X” receptors such as bexarotene potently reverse aberrant adhesion and niche mislocalization in vivo and induce differentiation and cell cycle arrest. Focal adhesion kinase inhibitors block the downstream integrin-mediated signaling, reverse adhesion, and niche mislocalization. Both agents act synergistically with TKIs to prolong survival of Ph+ ALL in mouse and human xenograft model, with long-term remission induced by focal adhesion kinase inhibitors. Therefore, these findings provide important new conceptual insights into the mechanisms by which IKZF1 alterations result in drug resistance and indicate that therapeutic strategies directed against the pathways deregulated by mutation, rather than attempting to restore IKZF1 expression directly, represent promising therapeutic approaches in this disease. Acute lymphoblastic leukemia (ALL) is the most common childhood tumor, accounting for approximately 4000 newly diagnosed cases in North America each year [1Hunger S.P. Mullighan C.G. Acute lymphoblastic leukemia in children.N Engl J Med. 2015; 373: 1541-1552Crossref PubMed Scopus (1067) Google Scholar]. ALL is more commonly of B progenitor than T lineage and is an expansion of immature lymphoid progenitors that results in effacement of normal hematopoiesis in the bone marrow with resulting pancytopenia and invasion of extramedullary sites. Both B-progenitor and T-lineage ALL comprise multiple subtypes with constellations of structural chromosomal alterations such as aneuploidy, rearrangements or deletions, and sequence mutations [2Hunger S.P. Mullighan C.G. Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine.Blood. 2015; 125: 3977-3987Crossref PubMed Scopus (195) Google Scholar]. Although the number of genetic alterations per case is lower than in many other tumors, each ALL genome typically harbors 10–30 nonsilent genetic changes that perturb key cellular pathways, including lymphoid maturation; tumor suppression; cell cycle regulation; cytokine receptor, tyrosine kinase, and/or Ras signaling; transcriptional regulation; and chromatin modification [3Zhang J. Mullighan C.G. Harvey R.C. et al.Mutations in the RAS signaling, B-cell development, TP53/RB1, and JAK signaling pathways are common in high risk B-precursor childhood acute lymphoblastic leukemia (ALL): a report from the Children's Oncology Group (COG) High-Risk (HR) ALL TARGET project.ASH Annual Meeting Abstracts. 2009; 114: 40Google Scholar]. The nature of each alteration and the temporal order of acquisition vary between ALL subtypes, but these pathways are perturbed in most B-ALL cases. Common forms of B-ALL in children are ALL with high hyperdiploidy (gains of at least five chromosomes), hypodiploidy with less than 44 chromosomes, t(12;21) encoding ETV6-RUNX1, t(1;19) encoding TCF3-PBX1 (and variants), rearrangement of KMT2A (MLL) to multiple partners, t(9;22) encoding BCR-ABL1, rearrangement of the cytokine receptor gene CRLF2 by IGH-CRLF2 rearrangement, or an interstitial deletion on pseudoautosomal region 1 of chromosome X/Y resulting in P2RY8-CRLF2 expression. A recently described subtype of ALL termed Ph-like or BCR-ABL1-like ALL, exhibits a gene expression profile similar to that of Ph+ ALL, but lacks BCR-ABL1 and instead harbors a range of rearrangements, deletions, and mutations activating at least 15 different cytokine receptor and kinase genes [4Den Boer M.L. van Slegtenhorst M. De Menezes R.X. et al.A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study.Lancet Oncol. 2009; 10: 125-134Abstract Full Text Full Text PDF PubMed Scopus (671) Google Scholar, 5Mullighan C.G. Su X. Zhang J. et al.Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia.N Engl J Med. 2009; 360: 470-480Crossref PubMed Scopus (1033) Google Scholar, 6Lympany P.A. Avila J.J. Mullighan C. Marshall S. Welsh K.I. du Bois R.M. Rapid genotyping of transforming growth factor beta1 gene polymorphisms in a UK Caucasoid control population using the polymerase chain reaction and sequence-specific primers.Tissue Antigens. 1998; 52: 573-578Crossref PubMed Scopus (31) Google Scholar, 7Roberts K.G. Li Y. Payne-Turner D. et al.Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.N Engl J Med. 2014; 371: 1005-1015Crossref PubMed Scopus (937) Google Scholar, 8Iacobucci I. Li Y. Roberts K.G. et al.Truncating erythropoietin receptor rearrangements in acute lymphoblastic leukemia.Cancer Cell. 2016; 29: 186-200Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 9Roberts K.G. Gu Z. Payne-Turner D. et al.High frequency and poor outcome of Philadelphia chromosome-like acute lymphoblastic leukemia in adults.J Clin Oncol. 2016; ([Epub ahead of print])Google Scholar]. These alterations are typically early initiating lesions in leukemogenesis and influence the likelihood of treatment success or failure: hyperdiploidy, ETV6-RUNX1, and TCF3-PBX1 are associated with high cure rates, whereas MLL-rearrangement, Ph+, and Ph-like leukemia are associated with poor outcome [7Roberts K.G. Li Y. Payne-Turner D. et al.Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.N Engl J Med. 2014; 371: 1005-1015Crossref PubMed Scopus (937) Google Scholar]. Moreover, Ph and Ph-like leukemia become more frequent with increasing age. Much effort has been dedicated to defining the cooperating lesions that act with founding chromosomal rearrangements to drive leukemogenesis and to understanding the nature of genetic alterations that influence treatment outcome. Alterations in genes encoding transcriptional regulators of B-lymphoid development are a hallmark of B-progenitor ALL, occurring in more than two-thirds of cases. The prevalence and type of these alterations are associated significantly with ALL subtype. PAX5 encodes paired box 5 and is targeted by deletions, point mutations, or translocations in approximately 30% of B-ALL cases. PAX5 is required for B-lineage commitment and maturation [10Nutt S.L. Heavey B. Rolink A.G. Busslinger M. Commitment to the B-lymphoid lineage depends on the transcription factor Pax5.Nature. 1999; 401: 556-562Crossref PubMed Scopus (1) Google Scholar] and the alterations observed in ALL result in loss-of-function or dominant-negative effects [11Mullighan C.G. Goorha S. Radtke I. et al.Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia.Nature. 2007; 446: 758-764Crossref PubMed Scopus (1382) Google Scholar] and promote B-ALL development in mouse models [12Dang J. Wei L. de Ridder J. et al.Pax5 is a tumor suppressor in mouse mutagenesis models of acute lymphoblastic leukemia.Blood. 2015; 125: 3609-3617Crossref PubMed Scopus (60) Google Scholar, 13Liu G.J. Cimmino L. Jude J.G. et al.Pax5 loss imposes a reversible differentiation block in B-progenitor acute lymphoblastic leukemia.Genes Dev. 2014; 28: 1337-1350Crossref PubMed Scopus (60) Google Scholar, 14Roberts K.G. Morin R.D. Zhang J. et al.Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia.Cancer Cell. 2012; 22: 153-166Abstract Full Text Full Text PDF PubMed Scopus (524) Google Scholar]. However, whereas these alterations clearly contribute to leukemogenesis, they are not associated with outcome in most studies of human leukemia [15Wu G. Broniscer A. McEachron T.A. et al.Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas.Nat Genet. 2012; 44: 251-253Crossref PubMed Scopus (1106) Google Scholar]. In contrast, IKZF1 alterations are less common in B-ALL, but are enriched in high-risk subtypes and associated with poor outcome. IKZF1 (encoding the founding member of the Ikaros family of zinc finger transcription factors) is mutated in approximately 15% of childhood B-ALL cases [11Mullighan C.G. Goorha S. Radtke I. et al.Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia.Nature. 2007; 446: 758-764Crossref PubMed Scopus (1382) Google Scholar, 16Mullighan C.G. Miller C.B. Radtke I. et al.BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros.Nature. 2008; 453: 110-114Crossref PubMed Scopus (812) Google Scholar], but is altered in more than 70% of cases of Ph+ lymphoid leukemia: either de novo childhood or adult Ph+ ALL or chronic myeloid leukemia (CML) at progression to lymphoid blast crisis [16Mullighan C.G. Miller C.B. Radtke I. et al.BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros.Nature. 2008; 453: 110-114Crossref PubMed Scopus (812) Google Scholar, 17Iacobucci I. Storlazzi C.T. Cilloni D. et al.Identification and molecular characterization of recurrent genomic deletions on 7p12 in the IKZF1 gene in a large cohort of BCR-ABL1-positive acute lymphoblastic leukemia patients: on behalf of Gruppo Italiano Malattie Ematologiche dell'Adulto Acute Leukemia Working Party (GIMEMA AL WP).Blood. 2009; 114: 2159-2167Crossref PubMed Scopus (176) Google Scholar, 18Tokunaga K. Yamaguchi S. Iwanaga E. et al.High frequency of IKZF1 genetic alterations in adult patients with B-cell acute lymphoblastic leukemia.Eur J Haematol. 2013; 91: 201-208Crossref PubMed Scopus (29) Google Scholar, 19van der Veer A. Zaliova M. Mottadelli F. et al.IKZF1 status as a prognostic feature in BCR-ABL1-positive childhood ALL.Blood. 2014; 123: 1691-1698Crossref PubMed Scopus (107) Google Scholar]. IKZF1 alterations are also common in Ph-like ALL [7Roberts K.G. Li Y. Payne-Turner D. et al.Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.N Engl J Med. 2014; 371: 1005-1015Crossref PubMed Scopus (937) Google Scholar, 9Roberts K.G. Gu Z. Payne-Turner D. et al.High frequency and poor outcome of Philadelphia chromosome-like acute lymphoblastic leukemia in adults.J Clin Oncol. 2016; ([Epub ahead of print])Google Scholar]. In both diseases, deletion of CDKN2A/CDKN2B encoding the tumor suppressors and cell cycle regulators ARF (p14), INK4A (p16), and INK4B (p15) are also observed in approximately 50% of cases. The majority of studies have shown that IKZF1 alterations are associated with poor outcome both in ALL cohorts comprising multiple subtypes and in BCR-ABL1 ALL, including cases treated with tyrosine kinase inhibitors (TKIs) [19van der Veer A. Zaliova M. Mottadelli F. et al.IKZF1 status as a prognostic feature in BCR-ABL1-positive childhood ALL.Blood. 2014; 123: 1691-1698Crossref PubMed Scopus (107) Google Scholar, 20Kuiper R.P. Waanders E. van der Velden V.H. et al.IKZF1 deletions predict relapse in uniformly treated pediatric precursor B-ALL.Leukemia. 2010; 24: 1258-1264Crossref PubMed Scopus (211) Google Scholar, 21Buitenkamp T.D. Pieters R. Gallimore N.E. et al.Outcome in children with Down's syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations.Leukemia. 2012; 26: 2204-2211Crossref PubMed Scopus (81) Google Scholar, 22Asai D. Imamura T. Suenobu S. et al.IKZF1 deletion is associated with a poor outcome in pediatric B-cell precursor acute lymphoblastic leukemia in Japan.Cancer Med. 2013; 2: 412-419Crossref PubMed Scopus (50) Google Scholar, 23Dorge P. Meissner B. Zimmermann M. et al.IKZF1 deletion is an independent predictor of outcome in pediatric acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol.Haematologica. 2013; 98: 428-432Crossref PubMed Scopus (121) Google Scholar, 24Krentz S. Hof J. Mendioroz A. et al.Prognostic value of genetic alterations in children with first bone marrow relapse of childhood B-cell precursor acute lymphoblastic leukemia.Leukemia. 2013; 27: 295-304Crossref PubMed Scopus (69) Google Scholar, 25van der Veer A. Waanders E. Pieters R. et al.Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL.Blood. 2013; 122: 2622-2629Crossref PubMed Scopus (215) Google Scholar, 26Volejnikova J. Mejstrikova E. Dorge P. et al.Ikaros (IKZF1) alterations and minimal residual disease at day 15 assessed by flow cytometry predict prognosis of childhood BCR/ABL-negative acute lymphoblastic leukemia.Pediatr Blood Cancer. 2013; 60: 420-427Crossref PubMed Scopus (21) Google Scholar, 27Yamashita Y. Shimada A. Yamada T. et al.IKZF1 and CRLF2 gene alterations correlate with poor prognosis in Japanese BCR-ABL1-negative high-risk B-cell precursor acute lymphoblastic leukemia.Pediatr Blood Cancer. 2013; 60: 1587-1592Crossref PubMed Scopus (54) Google Scholar, 28Beldjord K. Chevret S. Asnafi V. et al.Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia.Blood. 2014; 123: 3739-3749Crossref PubMed Scopus (228) Google Scholar, 29Olsson L. Castor A. Behrendtz M. et al.Deletions of IKZF1 and SPRED1 are associated with poor prognosis in a population-based series of pediatric B-cell precursor acute lymphoblastic leukemia diagnosed between 1992 and 2011.Leukemia. 2014; 28: 302-310Crossref PubMed Scopus (59) Google Scholar, 30Yano M. Imamura T. Asai D. et al.An overall characterization of pediatric acute lymphoblastic leukemia with CRLF2 overexpression.Genes Chromosomes Cancer. 2014; 53: 815-823Crossref PubMed Scopus (21) Google Scholar, 31Clappier E. Grardel N. Bakkus M. et al.IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children's Leukemia Group study 58951.Leukemia. 2015; 29: 2154-2161Crossref PubMed Scopus (71) Google Scholar, 32Kim M. Park J. Kim D.W. et al.Impact of IKZF1 deletions on long-term outcomes of allo-SCT following imatinib-based chemotherapy in adult Philadelphia chromosome-positive ALL.Bone Marrow Transplant. 2015; 50: 354-362Crossref PubMed Scopus (14) Google Scholar, 33Ribera J. Morgades M. Zamora L. et al.Prognostic significance of copy number alterations in adolescent and adult patients with precursor B acute lymphoblastic leukemia enrolled in PETHEMA protocols.Cancer. 2015; 121: 3809-3817Crossref PubMed Scopus (37) Google Scholar, 34Boer J.M. van der Veer A. Rizopoulos D. et al.Prognostic value of rare IKZF1 deletion in childhood B-cell precursor acute lymphoblastic leukemia: an international collaborative study.Leukemia. 2016; 30: 32-38Crossref PubMed Scopus (59) Google Scholar, 35Yang Y.L. Hung C.C. Chen J.S. et al.IKZF1 deletions predict a poor prognosis in children with B-cell progenitor acute lymphoblastic leukemia: A multicenter analysis in Taiwan.Cancer Sci. 2011; 102: 1874-1881Crossref PubMed Scopus (51) Google Scholar]. An exception is a subtype of ALL characterized by deregulation of the double homeobox gene DUX4 and the ETS family transcription factor ERG, in which IKZF1 alterations are common but not associated with poor outcome [36Yasuda T. Tsuzuki S. Kawazu M. et al.Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults.Nat Genet. 2016; 48: 569-574Crossref PubMed Scopus (168) Google Scholar, 37Zhang J. McCastlain K. Yoshihara H. et al.Deregulation of DUX4 and ERG in acute lymphoblastic leukemia.Nat Genet. 2016; 48: 1481-1489Crossref PubMed Scopus (180) Google Scholar]. A critical question in the field of B-ALL has been why IKZF1 alterations are selectively associated with poor outcome, particularly in forms of ALL driven by activated kinase signaling, and how this poor outcome might be mitigated. This remains true in the era of TKI therapy, which has improved outcomes for substantially Ph+ ALL [38Schultz K.R. Carroll A. Heerema N.A. et al.Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children's Oncology Group study AALL0031.Leukemia. 2014; 28: 1467-1471Crossref PubMed Scopus (303) Google Scholar, 39Arico M. Schrappe M. Hunger S.P. et al.Clinical outcome of children with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia treated between 1995 and 2005.J Clin Oncol. 2010; 28: 4755-4761Crossref PubMed Scopus (172) Google Scholar] and is showing promise in Ph-like ALL [7Roberts K.G. Li Y. Payne-Turner D. et al.Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.N Engl J Med. 2014; 371: 1005-1015Crossref PubMed Scopus (937) Google Scholar, 40Weston B.W. Hayden M.A. Roberts K.G. Tyrosine kinase inhibitor therapy induces remission in a patient with refractory EBF1-PDGFRB-positive acute lymphoblastic leukemia.J Clin Oncol. 2013; 31: e413-e416Crossref PubMed Scopus (181) Google Scholar]. Ikaros is a zinc finger transcription factor required for the development of all lymphoid lineages. It has eight exons, seven of which are coding (Fig. 1A). Exons 4–6 harbor four zinc fingers that bind DNA and the C-terminus of exon 8 contains two zinc fingers that mediate homodimerization of Ikaros and heterodimerization with other Ikaros family members such as Aiolos (IKZF3). The genetic alterations of IKZF1 in ALL are most commonly deletions. In approximately two-thirds of cases, these result in loss of function. In the remaining cases, focal deletions result in expression of an internally deleted isoform that lacks exons 4–7 and thus all DNA-binding zinc fingers, which mislocalizes Ikaros and acts as a dominant negative (Fig. 1A and 1B). Missense mutations in the DNA-binding domain have similar effects [41Churchman M.L. Low J. Qu C. et al.Efficacy of retinoids in IKZF1-mutated BCR-ABL1 acute lymphoblastic leukemia.Cancer Cell. 2015; 28: 343-356Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar].Figure 1Ikaros architecture and effects of perturbation. (A) Ikaros protein structure comprised of coding exons 2 through 8, including four N-terminal zinc fingers that comprise the DNA-binding domain and two C-terminal zinc fingers that are responsible for hetero- and homodimerization. (B) Immunofluorescence using an N-terminal specific anti-Ikaros antibody (green) and a DNA-binding stain, 4′,6-diamidino-2-phenylindole (DAPI; blue) showing punctate, nuclear staining of endogenous Ikaros in primary mouse Arf–/– BCR-ABL1+ pre-B cells transduced with empty vector (left panel) or IK6 (right panel, which lacks the DNA-binding domain and grossly mislocalizes to the cytoplasm. Scale bar indicates 5 μm. (C) Schematic of Ikaros dimerization, DNA binding, and association with the NuRD complex to repress the transcription of adhesion molecules and genes that restrict differentiation to allow proper developmental progression of lymphoid progenitors (top). This causes a loss of DNA-binding capability with the retention of the ability to dimerize and results in potent dominant-negative effects of IK6, resulting in inappropriate expression of genes that affect a block in differentiation and confer an adhesive phenotype to typically nonadherent lymphoid progenitors. (D) Schematic summary of the effects of Ikaros alterations in various engineered mouse models of BCR-ABL1+ B-ALL in vivo. Transduction of BCR-ABL1 into non-manipulated whole bone marrow of Ikzf1+/− or wild-type mice and transplantation directly back into syngeneic wild-type mice results in marked acceleration of B-ALL in an Ikzf1+/− background (left arm). IK6 cooperates with Arf loss in driving lymphoid leukemia, as demonstrated by transduction and transplantation of lineage-negative bone marrow cells from either wild-type Arf−/− mice with BCR-ABL1 and empty vector or IK6 (middle arm). BCR-ABL1-transformed pre-B cells from the indicated genotypes in combination with IK6 have varying degrees of sensitivity to tyrosine kinase inhibition with dasatinib (right arm).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Ikaros has multiple roles in transcriptional regulation that are likely cell-type and stage dependent, including transcriptional activation and repression, which are in part mediated by chromatin remodeling (Fig. 1C). Ikaros, with histone deacetylases and the Ikaros family member Aiolos, is part of the nucleosome remodeling and deacetylase (NuRD) complex that mediates histone deacetylation in a site-specific fashion dependent on the presence of Ikaros in the NuRD complex [42Mullighan C.G. Bardy P.G. New directions in the genomics of allogeneic hematopoietic stem cell transplantation.Biol Blood Marrow Transplant. 2007; 13: 127-144Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 43Kim J. Sif S. Jones B. et al.Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes.Immunity. 1999; 10: 345-355Abstract Full Text Full Text PDF PubMed Scopus (483) Google Scholar]. Ikaros also associates with polycomb repressor complex 2 (PRC2) independently of the NuRD complex [44Oravecz A. Apostolov A. Polak K. et al.Ikaros mediates gene silencing in T cells through Polycomb repressive complex 2.Nat Commun. 2015; 6: 8823Crossref PubMed Scopus (46) Google Scholar]. PRC2 mediates histone 3 lysine 27 (H3K27) trimethylation and transcriptional repression and loss of Ikaros in mouse thymocytes results in transcriptional derepression of hematopoietic stem cell (HSC) and NOTCH1 target genes [44Oravecz A. Apostolov A. Polak K. et al.Ikaros mediates gene silencing in T cells through Polycomb repressive complex 2.Nat Commun. 2015; 6: 8823Crossref PubMed Scopus (46) Google Scholar, 45Hu Y. Zhang Z. Kashiwagi M. et al.Superenhancer reprogramming drives a B-cell–epithelial transition and high-risk leukemia.Genes Dev. 2016; 30: 1971-1990Crossref PubMed Scopus (41) Google Scholar]. Prior mouse models of germline Ikzf1 mutations showed that loss-of-function alleles resulted in lack of lymphoid development and N-terminal zinc finger point mutations that perturb DNA binding resulted in an aggressive T-lineage lymphoproliferative disease [46Winandy S. Wu P. Georgopoulos K. A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma.Cell. 1995; 83: 289-299Abstract Full Text PDF PubMed Scopus (362) Google Scholar]. The propensity of Ikzf1-mutant mouse models to develop T-lineage malignancies may be related to the loss of normal transcriptional repression of NOTCH1 target genes in the T-cell lineage [47Geimer Le Lay A.S. Oravecz A. Mastio J. et al.The tumor suppressor Ikaros shapes the repertoire of notch target genes in T cells.Sci Signal. 2014; 7: ra28Crossref PubMed Scopus (57) Google Scholar]. However, these germline Ikzf1-mutant models do not develop B-cell neoplasms and, conversely, IKZF1 alterations are uncommon in human T-lineage ALL. Therefore, these studies clearly show that Ikaros is a critical regulator of normal lymphoid development and exerts complex transcriptional regulatory roles requiring chromatin remodeling, at least in mouse T-cell development. However, until recently, there were few data examining the role of Ikaros in the pathogenesis of pre-B ALL. In 2010, Virely et al. [48Virely C. Moulin S. Cobaleda C. et al.Haploinsufficiency of the IKZF1 (IKAROS) tumor suppressor gene cooperates with BCR-ABL in a transgenic model of acute lymphoblastic leukemia.Leukemia. 2010; 24: 1200-1204Crossref PubMed Scopus (72) Google Scholar] demonstrated in a transgenic model of BCR-ABL1 ALL that Ikzf1 haploinsufficiency accelerated the onset of leukemia, but without mechanistic insights or examination of the role of Ikzf1 alterations in responsiveness to therapy. To address these questions, we performed a series of experiments modeling the role of IKZF1 alterations in BCR-ABL1 ALL (Fig. 1D) with the goal of faithfully recapitulating the genetic alterations in human leukemia, examining the role in treatment response, and, ultimately, identifying new therapeutic approaches in this form of leukemia. Prior studies using retroviral or transgenic expression of BCR-ABL1 in hematopoietic progenitors have shown that this fusion oncoprotein promotes the development of a myeloproliferative neoplasm similar to CML, that retroviral expression in Arf−/− mouse pre-B cells results in a highly penetrant pre-B ALL, and that the latency of pre-B ALL in a transgenic model is reduced in the setting of Ikzf1 haploinsufficiency. To model faithfully the most common genetic lesions in BCR-ABL1 ALL, IKZF1 deletion or the presence of the dominant-negative isoform IK6 and CDKN2A/B deletion, we used multiple retroviral bone marrow transplantation approaches. These experiments used non-manipulated or lineage-negative bone marrow from a range of genetic backgrounds including loss of Ikzf1 and Arf [49Wang J.H. Nichogiannopoulou A. Wu L. et al.Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation.Immunity. 1996; 5: 537-549Abstract Full Text PDF PubMed Scopus (505) Google Scholar, 50Kamijo T. Zindy F. Roussel M.F. et al.Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF.Cell. 1997; 91: 649-659Abstract Full Text Full Text PDF PubMed Scopus (1385) Google Scholar], which was cotransduction with retroviruses expressing BCR-ABL1 together with IK6 or empty retroviral vector. These constructs coexpressed either green fluorescent protein (GFP) or red fluorescent protein to enable purification of cells for transplantation and/or luciferase to facilitate bioluminescent quantitation of disease burden. Using non-manipulated donor wild-type or Ikzf1+/− bone marrow, we confirmed that Ikaros haploinsufficiency resulted in acceleration of onset of pre-B (B220+ CD19+ BP1+) ALL (Fig. 1D) without detectable expansion of lymphoid precursor populations in Ikzf1+/− bone marrow, indicating that Ikaros acts as a tumor suppressor rather than expanding the pool of progenitor cells amenable to transformation. In addition, genomic an" @default.
• W2551657950 created "2016-11-30" @default.
• W2551657950 creator A5048744038 @default.
• W2551657950 creator A5057234924 @default.
• W2551657950 date "2017-02-01" @default.
• W2551657950 modified "2023-10-05" @default.
• W2551657950 title "Ikaros: Exploiting and targeting the hematopoietic stem cell niche in B-progenitor acute lymphoblastic leukemia" @default.
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• W2551657950 doi "https://doi.org/10.1016/j.exphem.2016.11.002" @default.
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