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 WuPatrick A. Brown, Erin M. Guest, David M. Barrett, Kathrin M. Bernt, Kai Tan

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish
Pages (from-to)2198-2211
Number of pages14
JournalBlood
Volume139
Issue number14
DOIs
StatePublished - 7 Apr 2022
Externally publishedYes

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