Single-cell multiomics reveals increased plasticity, resistant populations, and stem-cell–like blasts in KMT2A-rearranged leukemia
Changya Chen, Wenbao Yu, Fatemeh Alikarami, Qi Qiu, Chia-hui Chen, Jennifer Flournoy, Peng Gao, Yasin Uzun, Li Fang, James W. Davenport, Yuxuan Hu, Qin Zhu, Kai Wang, Clara Libbrecht, Alex Felmeister, Isaiah Rozich, Yang-yang Ding, Stephen P. Hunger, Carolyn A. Felix, Hao Wu, Patrick A. Brown, Erin M. Guest, David M. Barrett, Kathrin M. Bernt, Kai Tan
Abstract
KMT2A-rearranged (KMT2A-r) infant acute lymphoblastic leukemia (ALL) is a devastating malignancy with a dismal outcome, and younger age at diagnosis is associated with increased risk of relapse. To discover age-specific differences and critical drivers that mediate poor outcome in KMT2A-r ALL, we subjected KMT2A-r leukemias and normal hematopoietic cells from patients of different ages to single-cell multiomics analyses. We uncovered the following critical new insights: leukemia cells from patients <6 months have significantly increased lineage plasticity. Steroid response pathways are downregulated in the most immature blasts from younger patients. We identify a hematopoietic stem and progenitor-like (HSPC-like) population in the blood of younger patients that contains leukemic blasts and form an immunosuppressive signaling circuit with cytotoxic lymphocytes. These observations offer a compelling explanation for the ability of leukemias in young patients to evade chemotherapy and immune-mediated control. Our analysis also revealed preexisting lymphomyeloid primed progenitors and myeloid blasts at initial diagnosis of B-ALL. Tracking of leukemic clones in 2 patients whose leukemia underwent a lineage switch documented the evolution of such clones into frank acute myeloid leukemia (AML). These findings provide critical insights into KMT2A-r ALL and have clinical implications for molecularly targeted and immunotherapy approaches. Beyond infant ALL, our study demonstrates the power of single-cell multiomics to detect tumor intrinsic and extrinsic factors affecting rare but critical subpopulations within a malignant population that ultimately determines patient outcome.
Datasets
1. Global dataset of infant KMT2Ar B-ALL
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Source data
https://cellxgene.cziscience.com/collections/10ec9198-584e-4a7e-8a24-4a332915a4ef
Alias names
HTAN-CHOP, phs002371, PMID34864916, PMC8990373
Cite this study
Chen, C., Yu, W., Alikarami, F., Qiu, Q., Chen, C.H., Flournoy, J., Gao, P., Uzun, Y., Fang, L., Davenport, J.W. and Hu, Y., 2022. Single-cell multiomics reveals increased plasticity, resistant populations, and stem-cell–like blasts in KMT2A-rearranged leukemia. Blood, The Journal of the American Society of Hematology, 139(14), pp.2198-2211. https://doi.org/10.1182/blood.2021013442