Abla Oussama, Ries Rhonda E, Triche Tim, Gerbing Robert B, Hirsch Betsy, Raimondi Susana, Cooper Todd, Farrar Jason E, Buteyn Nathaniel, Harmon Lauren M, Wen Hong, Deshpande Aniruddha J, Kolb E Anders, Gamis Alan S, Aplenc Richard, Alonzo Todd, Meshinchi Soheil
Division of Hematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA.
Blood Adv. 2024 Apr 23;8(8):2005-2017. doi: 10.1182/bloodadvances.2023010805.
MLLT10 gene rearrangements with KMT2A occur in pediatric acute myeloid leukemia (AML) and confer poor prognosis, but the prognostic impact of MLLT10 in partnership with other genes is unknown. We conducted a retrospective study with 2080 children and young adults with AML registered on the Children's Oncology Group AAML0531 (NCT00372593) and AAML1031 trials (NCT01371981). Transcriptome profiling and/or karyotyping were performed to identify leukemia-associated fusions associated with prognosis. Collectively, 127 patients (6.1%) were identified with MLLT10 fusions: 104 (81.9%) with KMT2A::MLLT10, 13 (10.2%) with PICALM::MLLT10, and 10 (7.9%) X::MLLT10: (2 each of DDX3X and TEC), with 6 partners (DDX3Y, CEP164, SCN2B, TREH, NAP1L1, and XPO1) observed in single patients. Patients with MLLT10 (n = 127) demonstrated adverse outcomes, with 5-year event-free survival (EFS) of 18.6% vs 49% in patients without MLLT10 (n = 1953, P < .001), inferior 5-year overall survival (OS) of 38.2% vs 65.7% (P ≤ .001), and a higher relapse risk of 76% vs 38.6% (P < .001). Patients with KMT2A::MLLT10 had an EFS from study entry of 19.5% vs 12.7% (P = .628), and an OS from study entry of 40.4% vs 27.6% (P = .361) in those with other MLLT10 fusion partners. Patients with PICALM::MLLT10 had an EFS of 9.2% vs 20% in other MLLT10- without PICALM (X::MLLT10; P = .788). Patients with PICALM::MLLT10 and X::MLLT10 fusions exhibit a DNA hypermethylation signature resembling NUP98::NSD1 fusions, whereas patients with KMT2A::MLLT10 bear aberrations primarily affecting distal regulatory elements. Regardless of the fusion partner, patients with AML harboring MLLT10 fusions exhibit very high-risk features and should be prioritized for alternative therapeutic interventions.
MLLT10基因与KMT2A重排在小儿急性髓系白血病（AML）中出现，预后不良，但MLLT10与其他基因联合的预后影响尚不清楚。我们对登记在儿童肿瘤组AAML0531（NCT00372593）和AAML1031试验（NCT01371981）中的2080例儿童和青年AML患者进行了一项回顾性研究。进行转录组分析和/或核型分析以鉴定与预后相关的白血病相关融合。总共鉴定出127例（6.1%）MLLT10融合患者：104例（81.9%）为KMT2A::MLLT10，13例（10.2%）为PICALM::MLLT10，10例（7.9%）为X::MLLT10（DDX3X和TEC各2例），有6个伙伴（DDX3Y、CEP164、SCN2B、TREH、NAP1L1和XPO1）在单例患者中观察到。MLLT10患者（n = 127）显示出不良预后，5年无事件生存率（EFS）为18.6%，而无MLLT10患者（n = 1953）为49%（P <.001），5年总生存率（OS）较差，分别为38.2%和65.7%（P≤.001），复发风险更高，分别为76%和38.6%（P <.001）。KMT2A::MLLT10患者从研究入组开始的EFS为19.5%，而其他MLLT10融合伙伴患者为12.7%（P =.628），从研究入组开始的OS分别为40.4%和27.6%（P =.361）。PICALM::MLLT10患者在其他无PICALM的MLLT10患者（X::MLLT10）中的EFS为9.2%，而后者为20%（P =.788）。PICALM::MLLT10和X::MLLT10融合患者表现出类似于NUP98::NSD1融合的DNA高甲基化特征，而KMT2A::MLLT10患者主要存在影响远端调控元件的畸变。无论融合伙伴如何，携带MLLT10融合的AML患者均表现出极高风险特征，应优先考虑替代治疗干预措施。
