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 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 in the treatment of Ph+ ALL. Recent experimental mouse modeling of B-progenitor ALL has shown that IKZF1 alterations have multiple effects, including arresting differentiating, skewing lineage of leukemia from myeloid to lymphoid, and in Ph+ leukemia, conferring resistance to 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 specifically bind 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, and also reverse adhesion and niche mislocalization. Both agents act synergistically with TKI to prolong survival of Ph+ ALL in mouse and human xenograft model, with long term remission induced by FAK inhibitors. Thus, 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.

Dynamical modeling predicts an inflammation-inducible CXCR7+ B cell precursor with potential implications in lymphoid blockage pathologies

“…Full-size DOI: 10.7717/peerj.9902/ fig-1 & Mullighan, 2017;Joshi et al, 2014;Li et al, 2014). This assumption is consistent with the decrease in the capacity of pre-B cells to adhere to the VLA-4 receptor, VCAM-1, differentiation stage where expression of Aiolos occurs concomitant to Ikaros (Tokoyoda et al, 2004).…”

Deregulation of kinase signaling and lymphoid development in EBF1-PDGFRB ALL leukemogenesis

“… 43 For example, alterations of IKZF1 results in arrested differentiation, acquisition of a hematopoietic stem cell-like phenotype, and confers resistance to TKI therapy in models of BCR-ABL1 positive ALL. 44 Lesions in IKZF1 also activate expression of integrins and integrin signaling pathways. 43 , 45 Together, effects of the loss of IKZF1 compound the loss of EBF1.…”

Drug Resistance Biomarkers and Their Clinical Applications in Childhood Acute Lymphoblastic Leukemia

“…FAK activation results in migration, proliferation and survival, due to the activation of various signaling pathways such as Rac/Rho and PI3K/AKT. Furthermore, IKZF1-related dysregulation of NR3C1 gene, encoding GC receptor, involves in GC resistance (83). However, coding IKZF1 mutations have been identified in familial B-ALL and ∼0.9% of presumed sporadic pediatric B-ALL, most variants of which adversely affect IKZF1 function and response to treatment.…”