期刊
BLOOD
卷 139, 期 14, 页码 2198-2211出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2021013442
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类别
资金
- National Cancer Institute (NCI) HTAN [U2C CA233285]
- NCI [CA243072]
- Coco Foundation
- Department of Defense CDMRP award [W81XWH2010357]
- National Human Genome Research Institute [HG010646]
- National Heart, Lung, and Blood Institute [DP2-HL142044]
- Roberts Collaborative Rapid Grant
- Emerson Collective
- U.S. Department of Defense (DOD) [W81XWH2010357] Funding Source: U.S. Department of Defense (DOD)
The study revealed distinct characteristics of leukemia cells in KMT2A-r ALL patients of different ages. In younger patients, leukemia cells showed increased lineage plasticity, downregulation of steroid response pathways, and the presence of an HSPC-like population. These findings provide new insights into how leukemia cells in young patients evade treatment and immune control.
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.
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