title: Ikaros: Exploiting and targeting the hematopoietic stem cell niche in B-progenitor acute lymphoblastic leukemia.
abstract: 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.
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Churchman
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA. Electronic address: charles.mullighan@stjude.org.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D014644:Genetic Variation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D051740:Ikaros Transcription Factor / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism* / Q000628:therapy; D015398:Signal Transduction; D055153:Stem Cell Niche; D000072020:Synthetic Lethal Mutations
chemical_list: C497239:IKZF1 protein, human; D051740:Ikaros Transcription Factor; D051416:Focal Adhesion Protein-Tyrosine Kinases