Targeting Protein Lysine Methyltransferase G9A Impairs Self-Renewal of Chronic Myelogenous Leukemia Stem Cells via Upregulation of SOX6

Investigators found that protein lysine methyltransferase G9A was overexpressed in chronic myelogenous leukemia leukemia stem cells.
[Oncogene]
Zhou, M., Zhang, X., Liu, C., Nie, D., Li, S., Lai, P., & Jin, Y. (2021). Targeting protein lysine methyltransferase G9A impairs self-renewal of chronic myelogenous leukemia stem cells via upregulation of SOX6. Oncogene, 1–14. https://doi.org/10.1038/s41388-021-01799-1 Cite
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Anti-CLL1 Chimeric Antigen Receptor T Cell Therapy in Children with Relapsed/Refractory Acute Myeloid Leukemia

Scientists tested the safety and efficacy of chimeric antigen receptor T cell therapy in refractory/relapsed acute myeloid leukemia .
[Clinical Cancer Research]
Zhang, H., Wang, P., Li, Z., He, Y., Gan, W., & Jiang, H. (2021). Anti-CLL1 chimeric antigen receptor T cell therapy in children with relapsed/refractory acute myeloid leukemia. Clinical Cancer Research. https://doi.org/10.1158/1078-0432.CCR-20-4543 Cite
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Targeting Energy Metabolism in Cancer Stem Cells: Progress and Challenges in Leukemia and Solid Tumors

Scientists discuss the metabolic properties of leukemia stem cells and how targeting energy metabolism may provide more effective therapeutic regimens for leukemia patients.
[Cell Stem Cell]
Jones, C. L., Inguva, A., & Jordan, C. T. (2021). Targeting Energy Metabolism in Cancer Stem Cells: Progress and Challenges in Leukemia and Solid Tumors. Cell Stem Cell, 28(3), 378–393. https://doi.org/10.1016/j.stem.2021.02.013 Cite
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Functional Reconstruction of Human AML Reveals Stem Cell Origin and Vulnerability of Treatment-Resistant MLL-Rearranged Leukemia

HSC-derived Mixed Lineage Leukemia- acute myeloid leukemia gene fusions was highly resistant to chemotherapy and expressed elevated amounts of the multispecific anion transporter ABCC3.
[Science Translational Medicine]
Zeisig, B. B., Fung, T. K., Zarowiecki, M., Tsai, C. T., Luo, H., Stanojevic, B., Lynn, C., Leung, A. Y. H., Zuna, J., Zaliova, M., Bornhauser, M., Bonin, M. von, Lenhard, B., Huang, S., Mufti, G. J., & So, C. W. E. (2021). Functional reconstruction of human AML reveals stem cell origin and vulnerability of treatment-resistant MLL-rearranged leukemia. Science Translational Medicine, 13(582). https://doi.org/10.1126/scitranslmed.abc4822 Cite
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Inflammation-Driven Deaminase Deregulation Fuels Human Pre-Leukemia Stem Cell Evolution

Comparative whole-genome and whole-transcriptome sequencing analyses of FACS-purified pre-leukemia stem cells from myeloproliferative neoplasm patients reveal APOBEC3C upregulation, an increased C-to-T mutational burden, and hematopoietic stem and progenitor cell proliferation during progression, which can be recapitulated by lentiviral APOBEC3C overexpression.
[Cell Reports]
Jiang, Q., Isquith, J., Ladel, L., Mark, A., Holm, F., Mason, C., He, Y., Mondala, P., Oliver, I., Pham, J., Ma, W., Reynoso, E., Ali, S., Morris, I. J., Diep, R., Nasamran, C., Xu, G., Sasik, R., Rosenthal, S. B., … Jamieson, C. (2021). Inflammation-driven deaminase deregulation fuels human pre-leukemia stem cell evolution. Cell Reports, 34(4). https://doi.org/10.1016/j.celrep.2020.108670 Cite
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Metoclopramide Treatment Blocks CD93-Signaling-Mediated Self-Renewal of Chronic Myeloid Leukemia Stem Cells

The authors identified CD93 as an important regulator of self-renewal and proliferation of murine and human leukemia stem cells, but not hematopoietic stem cells.
[Cell Reports]
Riether, C., Radpour, R., Kallen, N. M., Bürgin, D. T., Bachmann, C., Schürch, C. M., Lüthi, U., Arambasic, M., Hoppe, S., Albers, C. E., Baerlocher, G. M., & Ochsenbein, A. F. (2021). Metoclopramide treatment blocks CD93-signaling-mediated self-renewal of chronic myeloid leukemia stem cells. Cell Reports, 34(4). https://doi.org/10.1016/j.celrep.2020.108663 Cite
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Studying Leukemia Stem Cell Properties and Vulnerabilities with Human iPSCs

Investigators discuss the lessons that can be learned about the leukemia stem cell (LSC) state, its plasticity, stability and genetic and epigenetic determinants from induced pluripotent stem cell (iPSC) modeling. They also discuss the practical and translational implications of exploiting acute myeloid leukemia (AML)-iPSCs to prospectively isolate large numbers of iLSCs for large-scale experiments, such as screens, and for discovery of new therapeutic targets specific to AML LSCs.
[Stem Cell Research]
Spyrou, N., & Papapetrou, E. P. (2021). Studying leukemia stem cell properties and vulnerabilities with human iPSCs. Stem Cell Research, 50, 102117. https://doi.org/10.1016/j.scr.2020.102117 Cite
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Small Molecule Inhibition of Dynamin-Dependent Endocytosis Targets Multiple Niche Signals and Impairs Leukemia Stem Cells

Researchers showed that Dynole 34-2, a potent inhibitor of Dynamin GTPase activity, could block transduction of key signaling pathways and overcome chemoresistance of leukemia stem cells.
[Nature Communications]
Tremblay, C. S., Chiu, S. K., Saw, J., McCalmont, H., Litalien, V., Boyle, J., Sonderegger, S. E., Chau, N., Evans, K., Cerruti, L., Salmon, J. M., McCluskey, A., Lock, R. B., Robinson, P. J., Jane, S. M., & Curtis, D. J. (2020). Small molecule inhibition of Dynamin-dependent endocytosis targets multiple niche signals and impairs leukemia stem cells. Nature Communications, 11(1), 6211. https://doi.org/10.1038/s41467-020-20091-6 Cite
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A Stem Cell Reporter Based Platform to Identify and Target Drug Resistant Stem Cells in Myeloid Leukemia

Investigators showed that a knock-in reporter mouse for the stem cell gene Musashi 2 allowed identification of leukemia stem cells in aggressive myeloid malignancies, and provided a strategy for defining their core dependencies.
[Nature Communications]
Spinler, K., Bajaj, J., Ito, T., Zimdahl, B., Hamilton, M., Ahmadi, A., Koechlein, C. S., Lytle, N., Kwon, H. Y., Anower-E-Khuda, F., Sun, H., Blevins, A., Weeks, J., Kritzik, M., Karlseder, J., Ginsberg, M. H., Park, P. W., Esko, J. D., & Reya, T. (2020). A stem cell reporter based platform to identify and target drug resistant stem cells in myeloid leukemia. Nature Communications, 11(1), 5998. https://doi.org/10.1038/s41467-020-19782-x Cite
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CC-90009, a Novel Cereblon E3 Ligase Modulator Targets Acute Myeloid Leukemia Blasts and Leukemia Stem Cells

Using a genome-wide CRISPR-Cas9 screen for effectors of CC-90009 response, researchers uncovered the ILF2 and ILF3 heterodimeric complex as a novel regulator of cereblon expression. Knockout of ILF2/ILF3 decreased the production of full-length cereblon protein via modulating CRBN mRNA alternative splicing, leading to diminished response to CC-90009.
[Blood]
Surka, C., Jin, L., Mbong, N., Lu, C.-C., Jang, I. S., Rychak, E., Mendy, D., Clayton, T., Tindall, E. A., Hsu, C., Fontanillo, C., Tran, E., Contreras, A., Ng, S. W.-K., Matyskiela, M. E., Wang, K., Chamberlain, P. P., Cathers, B., Carmichael, J., … Lu, G. (n.d.). CC-90009, a novel cereblon E3 ligase modulator targets acute myeloid leukemia blasts and leukemia stem cells. Blood. https://doi.org/10.1182/blood.2020008676 Cite
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SYK Inhibition Targets Acute Myeloid Leukemia Stem Cells by Blocking their Oxidative Metabolism

Investigators addressed the consequences of spleen tyrosine kinase (SYK) inhibition to leukemia stem-cell function and assessed SYK-associated pathways in acute myeloid leukemia cell biology.
[Cell Death & Disease]
Polak, A., Bialopiotrowicz, E., Krzymieniewska, B., Wozniak, J., Stojak, M., Cybulska, M., Kaniuga, E., Mikula, M., Jablonska, E., Gorniak, P., Noyszewska-Kania, M., Szydlowski, M., Piechna, K., Piwocka, K., Bugajski, L., Lech-Maranda, E., Barankiewicz, J., Kolkowska-Lesniak, A., Patkowska, E., … Juszczynski, P. (2020). SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism. Cell Death & Disease, 11(11), 1–15. https://doi.org/10.1038/s41419-020-03156-8 Cite
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