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

Chen C, Yu W, Alikarami F, Qiu Q, Chen C, Flournoy J, Gao P, Uzun Y, Fang L, Hu Y, Zhu Q, Wang K, Libbrecht C, Felmeister A, Rozich I, Ding Y, Hunger SP, Wu H, Brown PA, Guest EM, Barrett DM, Bernt KM, Tan K.
Preprint from
7 December 2020


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.