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Acute lymphoblastic leukemia

Cell of origin dictates aggression and stem cell number in acute lymphoblastic leukemia

Leukemia volume 32, pages 1860–1865 (2018)Cite this article

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Acute lymphoblastic leukemia (ALL) comprises a highly heterogeneous set of diseases that are defined by their cells of origin, stage of maturation arrest, and the underlying oncogenic driver pathways. Subclassification of lymphoid neoplasms is often based on the presumed cell of origin based on T and B progenitor gene expression. In general, T-ALL has a worse prognosis and requires more intensive therapies to achieve similar remission rates as their B-ALL counterparts [1, 2]. Given the common origin of these cells from committed lymphoid progenitors, investigators have suggested that the differences in clinical presentation of T-ALL and B-ALL are likely accounted for by the underlying differences in the oncogenic drivers of transformation. For example, T-ALLs often express oncogenic transcription factors and acquire activating NOTCH1 mutations that elevate MYC activity to drive tumor initiation and maintenance [3, 4]. By contrast, B-ALLs are more frequently driven by chromosomal rearrangements that create fusion oncogenes and have recurrent chromosomal aberrations [5]. Despite these differences, MYC is also commonly activated in human B-ALL [6] and drives leukemia initiation and growth in mouse models [7], suggesting important roles for this pathway in both T-ALL and B-ALL. It is clear that underlying oncogenic drivers exert important roles in regulating the functional characteristics of leukemia cells, including regulating the overall fraction of leukemia stem cells (LSCs) that drive continued tumor growth and relapse following therapy resistance. Yet, to date, the effect of cell lineage on influencing LSC number and self-renewal is largely unknown, accounted for in part, by lack of experimental models to address these questions.

Using this previously generated library of well-annotated monoclonal ALLs defined by Blackburn et al. [9], we selected leukemias that harbored high (>1%) and low numbers of LSCs (<1%, Supplemental Table 1) [9]. These leukemias are reported using the same nomenclature from Blackburn et al [9] and were subjected to bulk RNA sequencing. Principal Component Analysis (PCA) was then performed to identify molecular differences between clones. Principal Component 1 (PC1) and PC2 represent the top two gene expression profiles derived as dimensions from Principal Component Analysis. This analysis confirmed that replicate samples always segregated with one another, and more importantly, identified two easily discernable molecular subgroups of leukemia, labeled group 1 (in blue) and group 2 (in red, Fig. 1b). Interestingly, the two clusters in the PCA corresponded to significant differences in tumor behavior: group 1 leukemias had significantly shorter latency of leukemia regrowth in transplanted fish and had more LSCs when compared with group 2 (Fig. 1c, Wilcoxin Rank Order Test). Hierarchical clustering using the 100 most highly variable, positively and negatively correlated transcripts identified from PC1, affirmed the classification of two molecularly distinct ALL groups (Fig. 1d, Supplemental Table 2). Unexpectedly, GSEA analysis uncovered that PC1 was defined by T and B cell lineage genes, with T cell genes being highly expressed in the fast growing and high LSC containing leukemias while B cell genes were confined to leukemias with longer latency and low LSCs (Fig. 1d, e). PC2 genes comprised proliferation genes (Supplemental Table 3), identifying T-ALL clone 8.3 as having lower overall proliferative potential and likely accounting for its low percentage of LSCs.

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Acknowledgements

We thank Drs. Jessica Blackburn and Finola Moore for supplying zebrafish leukemias for RNA sequencing and Fluidigm single cell PCR analysis; the MGH Flow Cytometry Core for help with single cell sorting; Na Qu and Dr. Toshi Shioda for help with NextGen sequencing; and Dr. Antony Anselmo for superior bioinformatics analysis. This work is supported by NIH grant R24OD016761 and R01CA211734 (DML) and by the Fund for Scientific Research Flanders (FWO Vlaanderen, doctoral grant SL).

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  1. These authors contributed equally: Sowmya Iyer, Sara P. Garcia.

Authors and Affiliations

  1. Department of Pathology, Massachusetts General Hospital Research Institute, Boston, MA, 02114, USA

    Elaine G. Garcia, Sowmya Iyer, Sara P. Garcia, Ruslan I. Sadreyev & David M. Langenau

  2. Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, 02129, USA

    Elaine G. Garcia, Sowmya Iyer, Sara P. Garcia & David M. Langenau

  3. Harvard Stem Cell Institute, Boston, MA, 02114, USA

    Elaine G. Garcia, Sowmya Iyer, Sara P. Garcia & David M. Langenau

  4. Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA

    Elaine G. Garcia, Sowmya Iyer, Sara P. Garcia, Ruslan I. Sadreyev & David M. Langenau

  5. Cancer Research Institute Ghent (CRIG) and Center for Medical Genetics, Ghent University, Ghent, Belgium

    Siebe Loontiens & Frank Speleman

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  1. Elaine G. Garcia
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Correspondence to David M. Langenau.

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Garcia, E.G., Iyer, S., Garcia, S.P. et al. Cell of origin dictates aggression and stem cell number in acute lymphoblastic leukemia. Leukemia 32, 1860–1865 (2018). https://doi.org/10.1038/s41375-018-0130-0

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