Review

儿童急性白血病中的Menin抑制剂：全面综述及促进合作与全球社区共同进展的建议

Menin inhibitors in pediatric acute leukemia: a comprehensive review and recommendations to accelerate progress in collaboration with adult leukemia and the international community

LEUKEMIA

影响因子:13.4

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

DOI: 10.1038/s41375-024-02368-7

摘要

HOX和MEIS1家族基因异常表达（如在KMT2A重排、NUP98重排或NPM1突变的白血病中观察到）导致分化阻滞和白血病发展。HOX家族基因是生理性造血的关键调控因子，其表达受KMT2A与menin相互作用调控。Menin抑制剂通过阻断这种相互作用，抑制MEIS1及其他转录因子的异常表达，从而解除分化阻滞。Menin抑制剂在KMT2A重排和NPM1突变的急性白血病中显示出显著的临床疗效，有望解决多种儿童白血病亚型中的未满足需求。在本合作项目中，儿科与成人血液学/肿瘤学专家以及干细胞移植医生共同探索menin抑制剂在儿童白血病治疗中的潜力，整合前临床证据和全球临床试验的最新动态。我们还建议设计未来的国际化、包容性和高效的临床试验，将儿童纳入成人试验，以确保所有患有menin依赖性白血病的儿童和青少年都能获得这类有希望的治疗。

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.