Escherich Carolin S, Moriyama Takaya, Li Zhenhua, Hsiao Yu-Chih, Yang Wenjian, Li Yizhen, Reyes Noemi, Walker Megan, Budhraja Amit, Bhatara Sheetal, Diaz-Flores Ernesto, Stock Wendy, Paietta Elisabeth, Konopleva Marina Y, Kornblau Steven M, Litzow Mark R, Inaba Hiroto, Pui Ching-Hon, Opferman Joseph T, Loh Mignon L, Yu Jiyang, O'Brien Maureen M, Evans William E, Yang Jun J
Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN.
Department for Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine University, Duesseldorf, Germany.
Blood. 2025 Mar 13;145(11):1182-1194. doi: 10.1182/blood.2024026085.
Inotuzumab ozogamicin (InO) is an antibody-calicheamicin conjugate with striking efficacy in B-cell acute lymphoblastic leukemia (B-ALL). However, there is wide interpatient variability in treatment response, and the genetic basis of this variation remains largely unknown. Using a genome-wide CRISPR screen, we discovered that the loss of DNA nucleotidylexotransferase (DNTT) is a primary driver of InO resistance. Mechanistically, the downregulation of DNTT attenuated InO-induced DNA damage response, cell cycle arrest, and mitochondrial apoptotic priming, thereby ultimately leading to leukemia resistance to InO. Ex vivo leukemia InO sensitivity was highly associated with DNTT expression in ALL blasts with substantial intraleukemia heterogeneity as revealed by single-cell RNA sequencing. Among patients with B-ALL enrolled in the Children's Oncology Group trial AALL1621, we observed consistent DNTT downregulation in residual blasts following InO treatment. The selection of DNTT-low blasts by InO therapy was also recapitulated in vivo using patient-derived xenograft models. Collectively, our data indicate that DNTT is a key regulator of calicheamicin response in leukemia and thus a potential biomarker for individualizing InO therapy in B-ALL.
伊诺妥珠单抗奥佐米星（InO）是一种抗体-卡奇霉素偶联物，对B细胞急性淋巴细胞白血病（B-ALL）具有显著疗效。然而，患者间的治疗反应存在很大差异，这种差异的遗传基础仍 largely unknown。通过全基因组CRISPR筛选，我们发现DNA核苷酸外转移酶（DNTT）的缺失是InO耐药的主要驱动因素。从机制上讲，DNTT的下调减弱了InO诱导的DNA损伤反应、细胞周期停滞和线粒体凋亡启动，从而最终导致白血病对InO产生耐药性。如单细胞RNA测序所揭示的，体外白血病InO敏感性与ALL原始细胞中DNTT的表达高度相关，且白血病内部存在显著异质性。在儿童肿瘤学组试验AALL1621入组的B-ALL患者中，我们观察到InO治疗后残留原始细胞中DNTT持续下调。使用患者来源的异种移植模型在体内也再现了InO治疗对DNTT低表达原始细胞的选择。总体而言，我们的数据表明DNTT是白血病中卡奇霉素反应的关键调节因子，因此是B-ALL中InO个体化治疗的潜在生物标志物。
