No abstract

MYC oncogene is a transcription factor with a wide array of functions affecting cellular activities such as cell cycle, apoptosis, DNA damage response, and hematopoiesis. Due to the multi-functionality of MYC, its expression is regulated at multiple levels. Deregulation of this oncogene can give rise to a variety of cancers. In this review, MYC regulation and the mechanisms by which MYC adjusts cellular functions and its implication in hematologic malignancies are summarized. Further, we also discuss potential inhibitors of MYC that could be beneficial for treating hematologic malignancies.

IntroductionHemophilia A is the most common severe inherited bleeding disorder. Patients with this disease are treated with recombinant or plasma-derived factor VIII (FVIII), which allows them to lead relatively normal lives. 1 In approximately 25% of treated patients, however, the development of anti-FVIII antibodies (FVIII inhibitors) severely complicates FVIII replacement therapy and significantly increases morbidity within the hemophilia population. [2][3][4][5] These antibodies neutralize the procoagulant cofactor activity of FVIII or enhance its clearance from plasma. 5 In economically developed countries, there are 2 approaches to the clinical management of FVIII inhibitors: the treatment or prevention of bleeding and long-term immune tolerance induction (ITI). Bleeding is controlled with variably effective and expensive FVIII-bypassing agents, such as recombinant (r) FVIIa and FEIBA (FVIII-inhibitor bypassing agent). In contrast, ITI is usually attempted through the administration of FVIII at a dose and frequency that depends on the ITI protocol. 6 This treatment approach is practically challenging, costly, and can take months to years to become effective. In light of the significant limitations of the current treatment options, the development of effective, rapid, and economical ITI strategies is a clinical priority.Currently, the most consistent model to study FVIII inhibitors is the hemophilia A mouse (FVIII Ϫ/Ϫ ). [7][8][9] Repeated intravenous infusion of human FVIII into hemophilia A mice results in high titer inhibitor formation. This is a CD4 ϩ T cell-dependent process that requires costimulation. [9][10][11][12] The dependence on CD4 ϩ T cells for inhibitor formation also occurs in humans. Evidence of this first came from hemophilia A patients with FVIII inhibitors who were also HIV ϩ : as patient CD4 ϩ levels declined, there was concomitant disappearance of FVIII inhibitors. 13 Therefore, therapies that blocked T-cell activation seemed to be promising candidates to prevent inhibitor formation.Indeed, Qian et al demonstrated that FVIII Ϫ/Ϫ B7.2 Ϫ/Ϫ doubleknockout mice will not develop anti-FVIII antibodies (Abs) after repeated immunization with FVIII, and that blocking the CD80-CD28 costimulatory interaction with soluble cytotoxic T lymphocyte antigen-4 (CTLA-4)-immunoglobulin (Ig) in FVIII Ϫ/Ϫ mice also prevented inhibitor formation. 10 Additional studies in FVIII Ϫ/Ϫ mice showed that blockade of the CD40-CD40L interaction with anti-CD40L monoclonal Ab (mAb) also protects against FVIII inhibitor formation. 11,12 However, costimulatory blockade must be applied with each FVIII administration to maintain tolerance, and once the blockade is removed, the protective effect is lost. As the potential health risks of long-term costimulatory blockade have not yet been determined and because many hemophilia A patients are treated frequently with FVIII and would most likely need to coadminister blockade with each infusion, this therapy is not a viable option.To reach the clinic, a therapy that induces tole...

This study shows that tolerogenic presentation of cFVIII to the immune system can significantly reduce immunogenicity of the protein.

Previous studies have demonstrated that genetic factors play an important role in determining the likelihood of formation of anti-factor VIII (FVIII) antibodies in haemophilia A patients. We were interested in characterizing the spectrum of FVIII antibody formation and the primary and secondary immune responses after FVIII administration in two different exon 16-disrupted haemophilia A mouse strains, Balb/c and C57BL/6. Balb/c and C57BL/6 E16 haemophilia A mice were used in all experiments. Total FVIII antibodies and FVIII inhibitors were measured using ELISA and Bethesda assays respectively. T- and B-cell cytokines were quantified using ELISA and flow cytometry. FVIII antibodies, but not functional inhibitors were detectable 1 week after the first FVIII treatment in both strains. These antibodies mainly belonged to the IgM and IgA isotypes. After the fourth FVIII treatment, neutralizing anti-FVIII antibodies were detected in both mouse strains: Balb/c (mean inhibitory titer 58 BU) and C57BL/6 (mean inhibitory titer 82 BU). IgG1 levels were similar in both strains but the IgG2A and IgG2B subclasses were higher in C57BL/6 mice. The results of intracellular cytokine staining of T cells indicated that the FVIII-treated C57BL/6 mice produced more IL10 and Th1 cytokines than the FVIII-treated Balb/c mice. These studies show that C57BL/6 mice develop a stronger immune response towards FVIII than Balb/c mice. We propose that the enhanced Th1 and IL10 cytokine micro-environment induced in C57BL/6 mice is responsible for this difference. Therefore, genetic strain-dependent differences must be considered when evaluating immunological outcomes in mouse models of haemophilia A.