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]
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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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DYRK2 Controls a Key Regulatory Network in Chronic Myeloid Leukemia Stem Cells

Scientists discuss molecular maintenance in leukemia stem cells in chronic myeloid leukemia and provide a more in-depth discussion of the dual-specificity kinase DYRK2, which has been identified as a novel actionable checkpoint in a critical leukemic network.
[Experimental and Molecular Medicine]
Park, C. S., & Lacorazza, H. D. (2020). DYRK2 controls a key regulatory network in chronic myeloid leukemia stem cells. Experimental & Molecular Medicine, 1–10. https://doi.org/10.1038/s12276-020-00515-5 Cite
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Targeting Mitochondrial Respiration for the Treatment of Acute Myeloid Leukemia

Scientists discuss the relative dependency that acute myeloid leukemia (AML) cells have on mitochondrial function, and the ability to pivot this reliance to target important subsets of AML cells, including leukemia stem cells.
[Biochemical Pharmacology]
Carter, J. L., Hege, K., Kalpage, H. A., Edwards, H., Hüttemann, M., Taub, J. W., & Ge, Y. (2020). Targeting mitochondrial respiration for the treatment of acute myeloid leukemia. Biochemical Pharmacology, 114253. https://doi.org/10.1016/j.bcp.2020.114253 Cite
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The Role of Autophagy in Targeted Therapy for Acute Myeloid Leukemia

Scientists review studies on the role of autophagy in acute myeloid leukemia (AML) development and summarize the linkage between autophagy and several recurrent genetic abnormalities in AML, highlighting the potential of capitalizing on autophagy modulation in targeted therapy for AML.
[Autophagy]
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