Genetics and pathologic landscape of lineage switch of acute leukemia during therapy
Ting Zhou, Choladda V. Curry, Mahsa Khanlari, Min Shi, Wei Cui, Deniz Peker, Weina Chen, Endi Wang, Juehua Gao, Qi Shen, Wei Xie, Fatima Zahra Jelloul, Rebecca L. King, Yuan Ji, Xiaoqiong Wang, Chen Zhao, Ifeyinwa E. Obiorah, Elizabeth L. Courville, Eric Nomura, Sindhu Cherian, Mina L. Xu, Richard Burack, Hong-xing Liu, Elias Jabbour, Koichi Takahashi, Wei Wang, Sa A. Wang, Joseph D. Khoury, L. Jeffrey Medeiros, Shimin Hu
Abstract
Lineage switch in leukemia, characterized by a complete cell-fate conversion from one lineage to another, is associated with a dismal prognosis. The era of immunotherapy has witnessed a notable increase in its incidence, approaching 8% of B-ALL following anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy [ 1 ]. This significant challenge underscores the pressing need for a deeper understanding of lineage switch. The existing literature, primarily comprising case reports and small case series, fails to offer a comprehensive portrayal of the clinicopathological features of this phenomenon [ 1 , 2 , 3 , 4 , 5 ]. Furthermore, data on its genetic and molecular basis are scant, with the understanding largely limited to its association with KMT2A fusions and BCR::ABL1 [ 6 , 7 ]. Thus, we undertook a multi-institutional investigation into lineage switch in acute leukemias, with a two-fold aim: primarily, to achieve an in-depth understanding of its clinicopathologic features, a crucial step for identifying at-risk patients and shaping prevention and management strategies in susceptible populations; and secondly, to identify potential genetic drivers and gain insights into clonal evolution pathways of these leukemias, ultimately paving the way toward targeted therapies.