-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

1986 Mechanisms of Leukemia Stem Cell Plasticity Revealed By Single Cell Analysis

Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Poster II
Hematology Disease Topics & Pathways:
ALL, Leukemia, Diseases, Biological Processes, Lymphoid Malignancies
Sunday, December 6, 2020, 7:00 AM-3:30 PM

R. Grant Rowe, MD, PhD1*, George Q. Daley, MD, PhD2, Trista E. North, PhD1, William Marion1*, Yana Pikman, MD3, Marian H. Harris, MD, PhD4*, Vivian Morris1*, Edroaldo Lummertz da rocha, PhD5*, Alex K. Shalek, PhD6*, Travis Hughes6*, Prerana Sensharma1*, Dahai Wang1*, Patricia Sousa2*, Shannan Ho Sui7*, Sergey Naumenko7* and Renan Vinicius Da Silva8*

1Boston Children's Hospital, Boston, MA
2Division of Hematology/Oncology, Stem Cell Program, Boston Children's Hospital, Boston, MA
3Dana Farber Cancer Institute, Boston, MA
4Department of Pathology, Boston Children's Hospital, Boston, MA
5Federal University of Santa Catarina, Florianopolis, Brazil
6Massachusetts Institute of Technology, Cambridge, MA
7Harvard School of Public Health, Boston, MA
8Feseral University of Santa Catarina, Florianopolis, BRA

Leukemia stem cells (LSCs) are the subset of leukemic cells that drive leukemia progression, resist therapy, and remain latent to spark disease relapse. LSCs are quantified by efficiency of xenografting immunodeficient mice, a measurement that is predictive of leukemia outcome. Although LSCs have been previously thought to be rare and phenotypically primitive, recent data indicate that LSCs may actually be heterogeneous. Here, we use single-cell transcriptomics combined with limiting dilution xenotransplantation to dissect the ontogeny of MLL-rearranged B-lymphoblastic leukemia (MLL-r B-ALL), an aggressive form of childhood leukemia. Compared to acute myeloid leukemia (AML), LSCs are abundant in MLL-r B-ALL. Recapitulating the unique clinical behavior of this form of leukemia, MLL-r B-ALL cells undergo a B-lymphoid to myeloid lineage switch under chemotherapy pressure consistent with primitive, multipotent transcriptional programs present in LSCs. Although we identify rare, chemotherapy-resistant, primitive LSCs, we also observe LSCs emerging from more differentiated populations. These facultative LSCs self-renew and possess the capability to replenish the full cellular diversity of MLL-r B-ALL. Using CITE-seq, we find that stem cell programs can be fully uncoupled from immunophenotype in MLL-r B-ALL. In mechanistic studies, we find that the phenotypically differentiated LSCs that drive bottom-up reconstitution of the leukemic cellular ontogeny bear signatures of MYC activation and oxidative phosphorylation. We confirm recruitment of these pathways in actively reconstituting, phenotypically differentiated LSCs, and define a pathway by which MYC rewires metabolism in MLL-r B-ALL LSCs. We find that MYC is required for LSC plasticity in vitro and in vivo. Targeting oxidative metabolism impairs LSC engraftment, identifying a potential therapeutic intervention. We conclude that the high LSC content and dual lineage and LSC plasticities of MLL-r B-ALL contribute to its chemotherapy resistance and persistently poor outcomes.

Disclosures: Shalek: Honeycomb Biotechnologies: Consultancy, Current equity holder in publicly-traded company; Cellarity: Consultancy, Current equity holder in publicly-traded company; Repertoire Immune Medicines: Consultancy, Current equity holder in publicly-traded company; Merck: Consultancy; Orche Bio: Consultancy, Current equity holder in publicly-traded company; Dahlia Biosciences: Consultancy, Current equity holder in publicly-traded company.

*signifies non-member of ASH