Stephen P. Hunger, MD
Yesterday’s scientific session, “Turning Genetic Discoveries Into Therapy,” was well attended by hematologists interested in the development of new treatment strategies for benign and malignant blood disorders extending from obscure pediatric diseases to rare subtypes of leukemia to the royal disease of Europe.
Dr. David Teachey from the Children’s Hospital of Philadelphia discussed remarkable new findings in autoimmune lymphoproliferative syndrome (ALPS) showing that most patients have germline or somatic mutations in one of several genes in the Fas-mediated apoptosis pathway. These mutations lead to expansion of double-negative T cells (DNTs) with resulting lymphoproliferation and a propensity to develop secondary malignancies. New findings show phenotypic and genotypic overlap with autoimmune disorders such as Evans syndrome (multiple autoimmune cytopenias), expanding the spectrum of these disorders. Dr. Teachey noted that up to half of patients with Evan’s syndrome who have been tested have signs of ALPS. His group and others have shown that DNTs have defects in mammalian target of rapamycin (mTOR) signaling and that mTOR inhibitors can be extremely effective in ALPS. These developments may revolutionize the treatment of the ALPS family of disorders. Furthermore, the finding of somatic mutations is particularly intriguing and suggests that we need to think about how “benign” hematologic disorders overlap with lymphoid malignancies. Dr. Teachey stated, “It is exciting to be working on ALPS when collaborative international research has led to new insights into ALPS biology and remarkable progress with targeted therapies that are improving quality of life for these children.”
Dr. Ronald Stam of Erasmus Medical Center in Rotterdam, Netherlands, discussed the particularly virulent subtype of pediatric leukemias that contain translocations of the chromosome 11q23 gene MLL. These leukemias have a short latency and occur commonly in infants and in secondary leukemias that arise after topoisomerase II inhibitor therapy. The short latency and paucity of accompanying genetic lesions in MLL-rearranged leukemias have suggested that few cooperating genetic events may be required in this leukemia subtype. However, Dr. Stam and others have found that MLL-rearranged leukemias have unique gene expression patterns that are largely due to epigenetic alterations caused by abnormal histone modifications and/or alterations in methylation driven by MLL fusion proteins. Dr. Stam and others have shown that epigenetic therapies (demethylating agents and histone deactylase inhibitors or HDACi) can induce cell death and potentiate the effect of traditional cytotoxic chemotherapy. Dr. Stam remarked that “MLL-rearranged infant ALL is characterized by abnormal epigenetic changes and responds remarkably well to epigenetic drugs such as demethylating agents and HDACi.” Thus, rather than testing higher and higher doses of chemotherapy, a strategy that has been relatively ineffective for MLL-rearranged leukemias, the best approach might be to use less chemotherapy in combination epigenetic therapy.
Dr. David Lillicrap from Queen’s University discussed hemophilia A (factor VIII deficiency) and B (factor IX deficiency). In the past year, genetic archeology has shown that the royal disease of Europe was hemophilia B caused by a novel point mutation. Perhaps the most famous hemophiliac was Alexei Nikolaevich, the young son of the last Russian czar. Dr. Lillicrap noted that Alexei “was likely in severe pain most of the time, despite the best efforts of Rasputin.” The hemophilias are now considered prototypic models of genetic disease and new therapies. Cloning of the factor VIII and IX genes led to the development of recombinant clotting factor concentrates that have revolutionized treatment for hemophilia. Bioengineering is now focused on development of new second- and later-generation concentrates with longer half-life and, perhaps, reduced immunogenicity that could improve the lives of patients. In parallel, hemophilia has served as a paradigm disease for gene therapy because an increase in level of factor VIII (or IX) from < 1 percent to 5 percent would substantially ameliorate clinical manifestations of the disease. Progress in this area has occurred more slowly than hoped, but new developments suggest the potential therapeutic utility of a variety of different gene therapy approaches.
Dr. Hunger indicated no relevant conflicts of interest.