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.

HOX 和 MEIS1 家族基因的异常表达，如 KMT2A 重排、NUP98 重排或 NPM1 突变的白血病所见，导致分化停滞和白血病发展。HOX 家族基因是生理造血的重要守门人，其表达受 KMT2A 和 menin 相互作用的调节。Menin 抑制剂阻断这种相互作用，下调 MEIS1 和其他转录因子的异常表达，从而释放分化阻滞。Menin 抑制剂对 KMT2A 重排和 NPM1 突变的急性白血病显示出显著的临床疗效，有望解决各种儿科白血病亚型中未满足的需求。在这项合作计划中，儿科和成人血液学家/肿瘤学家以及干细胞移植医生联合了他们的专业知识，在国际上探索 menin 抑制剂在儿科白血病治疗中的潜力。我们的工作旨在提供 menin 抑制剂的全面临床概述，整合正在进行的全球临床试验的临床前证据和见解。此外，我们提出了未来国际化、包容性和高效的临床试验设计，将儿科人群纳入成人试验，以确保所有患有 menin 依赖性白血病的儿童和青少年都能广泛获得这种有前途的疗法。