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Collection and Expansion of Stem Cells
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Recent data indicate that a variety of regulatory molecules that are active in early development, homeobox (HOX) transcription factors, may also play a role in the maintenance of stem cell self-renewal. Multiple HOX family members are expressed in the most primitive hematopoietic stem cell-enriched populations and their expression is down regulated in terminally differentiating CD34- cells.63 Overexpression of the homeobox gene, Hoxb4, in murine64-66 and human cord blood67 stem cells leads to enhanced proliferation of clonogenic progenitors in vitro and an enhanced ability to regenerate the most primitive stem cell compartment following serial transplantation in mice. Importantly, none of the mice in these experiments demonstrated hematological abnormalities following transplantation. HOXB4-transduced murine bone marrow cells led to rapid, extensive and highly polyclonal stem cell expansion in vitro resulting in a 1000-fold net increase of stem cells that retained full lymph-myeloid repopulating potential.68 Together these data suggest that HOXB4 overexpression enhances the rate of stem cell expansion without impairing normal differentiation or causing transformation. Other members of the HOX family, including HOXC4,69 HOXa9,70 LIM-homeobox 2 (LH2)71 and HOX1172 have been shown to have similar effects as HOX4B on stem and early progenitor cell expansion, but in some cases led to immortalization71,72 or transformation70 after prolonged expression. Recent review articles provide an extensive description of the role of HOX genes in normal hematopoiesis and leukemogenesis.73,74 Together these findings suggest exciting new areas for genetic manipulation of HOX genes in hematopoietic stem cell regulation, and in the case of HOXB4, perhaps for therapeutic stem cell expansion.
AID Biology: A pathological and clinical perspective
Published in International Reviews of Immunology, 2018
Meenal Choudhary, Anubhav Tamrakar, Amit Kumar Singh, Monika Jain, Ankit Jaiswal, Prashant Kodgire
AID is expressed constitutively in B-cell lymphoma and leukemia, and its expression is accordingly regulated in malignant cells with genomic instability. Blimp-1 is a gene that down-regulates AID expression along with shutting off the expression of oncogenes BCL6 and turns on plasma cell genes XBP-1 [91]. Strikingly, expression of AID is a critical issue in both normal and malignant B-cell. In fact, a normal B-cell becomes cancerous as soon as the level of AID is deregulated in the cell. Transcription factor HoxC4 binds directly to the promoter of AID gene, thereby up regulating its expression with increased SHM and CSR preferentially in germinal center B-cells [92].
Transcriptional regulation of B cell class-switch recombination: the role in development of noninfectious complications
Published in Expert Review of Clinical Immunology, 2022
Stelios Vlachiotis, Hassan Abolhassani
TLR agonists along with BCR signaling can potentiate CSR in human naive B cells, suggesting that TLR ligation could be a third signal along with T cell help, in the form of co-stimulatory molecules and cytokines [60]. In line with that, TLR9 engagement on human B cells initiates germline transcription of Cγ1, Cγ2, and Cγ3, a process associated with increased AID transcription, through the non-canonical NF-κB pathway, and cooperates with IL-10 through STATs and IRFs to promote class-switching to IgG1, IgG2, and IgG3, respectively [61]. On the same study, BCR engagement, along with IL-10, CD40L, and BAFF stimulation, was able to enhance IgG class-switching. Subsequent NF-κB activation leads to Hoxc4 expression, which binds to the region I of the Aicda promoter to enhance AID expression; an effect furtherly enhanced by estrogen-mediated expression of Hoxc4 [62–64]. In line with that, Hoxc4 expression is upregulated upon CD40 ligation or lipopolysaccharide (LPS, activator of TLR4) plus IL-4 stimulation of human B cells, with Hoxc4-deficient Ramos cells displaying severely reduced CSR; an effect, however, rescued by forced AID expression [65]. HOXC4 upregulation has also been reported in human autoimmunity (in systemic lupus erythematosus patients’ B cells), with a several-fold correlational increase in HOXC4 and AID, compared to healthy controls [66]. As autoimmune patients have high-affinity class-switched auto-Abs, and a Hoxc4-deficient SLE-prone mouse model (Hoxc4−/− MRL/Fas lpr/lpr) displays decreased CSR and SHM, HOXC4 may have a similar role in human CSR; however, HOXC4-deficient patients with immunodeficiency characteristics have not been reported to date. Aberrant expression of AID and NF-κB signaling has also been reported in cases of B cell lymphoma and gastric cancer [67–69], highlighting both the importance of NF-κB signaling and the severity of aberrant AID expression and its off-target effects.