小儿急性白血病的梅宁抑制剂：一项全面的评论和建议，以加速与成人白血病和国际社会合作的进步
Menin inhibitors in pediatric acute leukemia: a comprehensive review and recommendations to accelerate progress in collaboration with adult leukemia and the international community
影响因子:13.40000
分区:医学1区 Top / 血液学1区 肿瘤学2区
发表日期:2024 Oct
作者:
Branko Cuglievan, Hagop Kantarjian, Jeffrey E Rubnitz, Todd M Cooper, C Michel Zwaan, Jessica A Pollard, Courtney D DiNardo, Tapan M Kadia, Erin Guest, Nicholas J Short, David McCall, Naval Daver, Cesar Nunez, Fadi G Haddad, Miriam Garcia, Kapil N Bhalla, Abhishek Maiti, Samanta Catueno, Warren Fiskus, Bing Z Carter, Amber Gibson, Michael Roth, Sajad Khazal, Priti Tewari, Hussein A Abbas, Wallace Bourgeois, Michael Andreeff, Neerav N Shukla, Danh D Truong, Jeremy Connors, Joseph A Ludwig, Janine Stutterheim, Elisabeth Salzer, Kristian L Juul-Dam, Koji Sasaki, Kris M Mahadeo, Sarah K Tasian, Gautam Borthakur, Samantha Dickson, Nitin Jain, Elias Jabbour, Soheil Meshinchi, Guillermo Garcia-Manero, Farhad Ravandi, Eytan M Stein, E Anders Kolb, Ghayas C Issa
摘要
如在KMT2A重新培训，NUP98重新延长或NPM1突变的白血病所示，HOX和MEIS1家族基因的异常表达导致了阻碍的分化和白血病的发展。 Hox家族基因是生理造血的必不可少的守门人，它们的表达受KMT2A与Menin之间的相互作用的调节。 Menin抑制剂阻止了这种相互作用，下调了MEIS1和其他转录因子的异常表达，从而释放了分化块。 Menin抑制剂显示出针对KMT2A重新培养和NPM1突变的急性白血病的显着临床功效，具有满足各种儿科白血病亚型未满足需求的潜力。在这项合作倡议中，儿科和成人血液学家/肿瘤学家以及干细胞移植医师将其专业知识结合在一起，以探索梅宁抑制剂在国际小儿白血病治疗中的潜力。我们的努力旨在提供梅宁抑制剂的全面临床概述，整合临床前证据和正在进行的全球临床试验的见解。此外，我们提出了未来的国际，包容和有效的临床试验设计，并将小儿种群整合在成人试验中，以确保为所有依赖Menin依赖性白血病的儿童和青少年广泛使用这种有希望的疗法。
Abstract
Aberrant expression of HOX and MEIS1 family genes, as seen in KMT2A-rearranged, NUP98-rearranged, or NPM1-mutated leukemias leads to arrested differentiation and leukemia development. HOX family genes are essential gatekeepers of physiologic hematopoiesis, and their expression is regulated by the interaction between KMT2A and menin. Menin inhibitors block this interaction, downregulate the abnormal expression of MEIS1 and other transcription factors and thereby release the differentiation block. Menin inhibitors show significant clinical efficacy against KMT2A-rearranged and NPM1-mutated acute leukemias, with promising potential to address unmet needs in various pediatric leukemia subtypes. In this collaborative initiative, pediatric and adult hematologists/oncologists, and stem cell transplant physicians have united their expertise to explore the potential of menin inhibitors in pediatric leukemia treatment internationally. Our efforts aim to provide a comprehensive clinical overview of menin inhibitors, integrating preclinical evidence and insights from ongoing global clinical trials. Additionally, we propose future international, inclusive, and efficient clinical trial designs, integrating pediatric populations in adult trials, to ensure broad access to this promising therapy for all children and adolescents with menin-dependent leukemias.