Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL–AF4 fusion protein

Proteasome inhibitors bortezomib and carfilzomib are approved for the treatment of multiple myeloma and mantle cell lymphoma and have demonstrated clinical efficacy for the treatment of acute lymphoblastic leukemia (ALL). The t(4;11)(q21;q23) chromosomal translocation that leads to the expression of MLL–AF4 fusion protein and confers a poor prognosis, is the major cause of infant ALL. This translocation sensitizes tumor cells to proteasome inhibitors, but toxicities of bortezomib and carfilzomib may limit their use in pediatric patients. Many of these toxicities are caused by on-target inhibition of proteasomes in non-lymphoid tissues (e.g., heart muscle, gut, testicles). We found that MLL–AF4 cells express high levels of lymphoid tissue-specific immunoproteasomes and are sensitive to pharmacologically relevant concentrations of specific immunoproteasome inhibitor ONX-0914, even in the presence of stromal cells. Inhibition of multiple active sites of the immunoproteasomes was required to achieve cytotoxicity against ALL. ONX-0914, an inhibitor of LMP7 (ß5i) and LMP2 (ß1i) sites of the immunoproteasome, and LU-102, inhibitor of proteasome ß2 sites, exhibited synergistic cytotoxicity. Treatment with ONX-0914 significantly delayed the growth of orthotopic ALL xenograft tumors in mice. T-cell ALL lines were also sensitive to pharmacologically relevant concentrations of ONX-0914. This study provides a strong rationale for testing clinical stage immunoproteasome inhibitors KZ-616 and M3258 in ALL

Genetic analysis of line "Lupinoid" of garden pea (Pisum sativum L.)

В исследовании генетического контроля формирования особого типа соцветия линии гороха посевного «Люпиноид» применен гибридологический метод. Показано, что формирование такого соцветия — обусловлено — комплементарным взаимодействием рецессивных аллелей двух генов, один из которых связан с ограничением размеров побеговой апикальной меристемы, а второй контролирует пролиферацию главной оси. Обсуждается возможность использования данной линии в исследовании фундаментальных и прикладных аспектов генетики растений.The hybridological method was used to analyze the genetic control of inflorescence development in pea line "Lupinoid". It was demonstrated that recessive alleles of two genes take part in formation of the special inflorescence type. One of these genes limits size of stem apical meristem, the another one provides axis proliferation in wild type plants. Some conclusions connected with perspectives of usage of analyzed line in plant breeding were also discussed