Single-cell multiomics reveals increased plasticity, resistant populations, and stem-cell–like blasts in KMT2A-rearranged leukemia

• Published in: Blood Vol. 139; no. 14; pp. 2198 - 2211
• Main Authors: Chen, Changya, Yu, Wenbao, Alikarami, Fatemeh, Qiu, Qi, Chen, Chia-hui, Flournoy, Jennifer, Gao, Peng, Uzun, Yasin, Fang, Li, Davenport, James W., Hu, Yuxuan, Zhu, Qin, Wang, Kai, Libbrecht, Clara, Felmeister, Alex, Rozich, Isaiah, Ding, Yang-yang, Hunger, Stephen P., Felix, Carolyn A., Wu, Hao, Brown, Patrick A., Guest, Erin M., Barrett, David M., Bernt, Kathrin M., Tan, Kai
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.04.2022; American Society of Hematology
• Subjects: Antineoplastic Agents - therapeutic use; Gene Rearrangement; Humans; Immunotherapy; Infant; Leukemia, Myeloid, Acute - genetics; Lymphoid Neoplasia; Myeloid-Lymphoid Leukemia Protein - genetics; Myeloid-Lymphoid Leukemia Protein - metabolism; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2021013442

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. •Single-cell multiomics analysis reveals higher plasticity and stem-cell-like blasts in younger KMT2A-r ALL patients with worse prognosis.•The most immature leukemic cells exhibit steroid resistance and stem–cell-like cells contribute to immune evasion in younger patients. [Display omitted]