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Single-cell multi-omics reveals elevated plasticity and stem-cell-like blasts relevant to the poor prognosis of KMT2A-rearranged leukemia

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Date: 7th December 2020 | Source: bioRxiv

Authors: Changya Chen, Wenbao Yu, Fatemeh Alikarami, Qi Qiu, Chia-hui Chen, Jennifer Flournoy, Peng Gao, Yasin Uzun, Li Fang, Yuxuan Yu, Qin Zhu, Kai Wang, Clara Libbrecht, Alex Felmeister, Isaiah Rozich, Yang-yang Ding, Stephan P Hunger, Hao Wu, Patrick A Brown, Erin M Guest, David M Barrett, Kathrin Maria Bernt, Kai Tan.

Infant ALL is a devastating malignancy caused by rearrangements of the KMT2A gene (KMT2A-r) in approximately 70% of patients. The outcome is dismal and younger age at diagnosis is associated with increased risk of relapse.

To discover age-specific differences and critical drivers that mediate the poor outcome in KMT2A-r ALL, we subjected KMT2A-r leukemias and normal hematopoietic cells from patients of different ages to multi-omic single cell analysis using scRNA-Seq, scATAC-Seq and snmC-Seq2.

We uncovered the following critical new insights: Leukemia cells from infants younger than 6 months have a greatly increased lineage plasticity and contain a hematopoietic stem and progenitor-like (HSPC-like) population compared to older infants. We identified an immunosuppressive signaling circuit between the HSPC-like blasts and cytotoxic lymphocytes in younger patients. Both observations offer a compelling explanation for the ability of leukemias in young infants to evade chemotherapy and immune mediated control. Our analysis also revealed pre-existing lymphomyeloid primed progenitor and myeloid blasts at initial diagnosis of B-ALL. Tracking of leukemic clones in two patients whose leukemia underwent a lineage switch documented the evolution of such clones into frank AML.

These findings provide critical insights into KMT2A-r ALL and have potential clinical implications for targeted inhibitors or multi-target immunotherapy approaches. Beyond infant ALL, our study demonstrates the power of single cell multi-omics 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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