Temporal Multiomic Modeling Reveals a B-Cell Receptor Proliferative Program in Chronic Lymphocytic Leukemia

Using an original ex vivo model of B-cell receptor-induced proliferation of chronic lymphocytic leukemia cells, researchers generated 108 temporal transcriptional and proteomic profiles from one hour up to four days after BCR activation.
[Leukemia]
Schleiss, C., Carapito, R., Fornecker, L.-M., Muller, L., Paul, N., Tahar, O., Pichot, A., Tavian, M., Nicolae, A., Miguet, L., Mauvieux, L., Herbrecht, R., Cianferani, S., Freund, J.-N., Carapito, C., Maumy-Bertrand, M., Bahram, S., Bertrand, F., & Vallat, L. (2021). Temporal multiomic modeling reveals a B-cell receptor proliferative program in chronic lymphocytic leukemia. Leukemia, 1–12. https://doi.org/10.1038/s41375-021-01221-5 Cite
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YBX1 Is Required for Maintaining Myeloid Leukemia Cell Survival by Regulating BCL2 Stability in an m6A-Dependent Manner

Investigators showed that YBX1 was specifically required for maintaining myeloid leukemia cell survival in an m6A-dependent manner.
[Blood]
Feng, M., Xie, X., Han, G., Zhang, T., Li, Y., Li, Y., Yin, R., Wang, Q., Zhang, T., Wang, P., Hu, J., Cheng, Y., Gao, Z., Wang, J., Chang, J., Cui, M., Gao, K., Chai, J., Liu, W., … Zhang, H. (2021). YBX1 is required for maintaining myeloid leukemia cell survival by regulating BCL2 stability in an m6A-dependent manner. Blood, blood.2020009676. https://doi.org/10.1182/blood.2020009676 Cite
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Very Long Chain Fatty Acid Metabolism Is Required in Acute Myeloid Leukemia

Genetic attenuation or pharmacological inhibition of VLCAD hindered mitochondrial respiration and fatty acid oxidation contribution to the TCA cycle, resulting in decreased viability, proliferation, clonogenic growth and acute myeloid leukemia cell engraftment.
[Blood]
Tcheng, M., Roma, A., Ahmed, N., Smith, R. W., Dr, Jayanth, P., Minden, M. D., Schimmer, A. D., Hess, D. A., Hope, K., Akhtar, T., Bohrnsen, E., D’Alessandro, A., Mohsen, A.-W., Vockley, J., & Spagnuolo, P. A. (2021). Very long chain fatty acid metabolism is required in acute myeloid leukemia. Blood, blood.2020008551. https://doi.org/10.1182/blood.2020008551 Cite
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Oxidative Phosphorylation Enhances the Leukemogenic Capacity and Resistance to Chemotherapy of B Cell Acute Lymphoblastic Leukemia

B cell acute lymphoblastic leukemia (B-ALL) cells with a low SoNar ratio had enhanced mitochondrial respiration capacity, mainly resided in the vascular niche, and were enriched with more functional leukemia-initiating cells than that of SoNar-high cells in a murine B-ALL model.
[Science Advances]
Chen, C., Hao, X., Lai, X., Liu, L., Zhu, J., Shao, H., Huang, D., Gu, H., Zhang, T., Yu, Z., Xie, L., Zhang, X., Yang, Y., Xu, J., Zhao, Y., Lu, Z., & Zheng, J. (2021). Oxidative phosphorylation enhances the leukemogenic capacity and resistance to chemotherapy of B cell acute lymphoblastic leukemia. Science Advances, 7(11), eabd6280. https://doi.org/10.1126/sciadv.abd6280 Cite
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Genome Editing of Donor-Derived T-Cells to Generate Allogenic Chimeric Antigen Receptor-Modified T Cells: Optimizing αβ T Cell-Depleted Haploidentical Hematopoietic Stem Cell Transplantation

Using genome editing with Cas9 ribonucleoprotein and adeno-associated virus serotype 6, the authors integrated a CD19-specific chimeric antigen receptor in-frame into the TRAC locus.
[Haematologica]
Wiebking, V., Lee, C. M., Mostrel, N., Lahiri, P., Bak, R., Bao, G., Roncarolo, M. G., Bertaina, A., & Porteus, M. H. (2021). Genome editing of donor-derived T-cells to generate allogenic chimeric antigen receptor-modified T cells: Optimizing αβ T cell-depleted haploidentical hematopoietic stem cell transplantation. Haematologica, 106(3), 847–858. https://doi.org/10.3324/haematol.2019.233882 Cite
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The Application of BH3 Mimetics in Myeloid Leukemias

As the number and variety of available BH3 mimetics increases, and investigations into applying these novel inhibitors to treat myeloid leukemias continue apace the need to evaluate where the science currently stands in this rapidly expanding field is clear.
[Cell Death & Disease]
Parry, N., Wheadon, H., & Copland, M. (2021). The application of BH3 mimetics in myeloid leukemias. Cell Death & Disease, 12(2), 1–13. https://doi.org/10.1038/s41419-021-03500-6 Cite
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SUMOylation Disassembles the Tetrameric Pyruvate Kinase M2 to Block Myeloid Differentiation of Leukemia Cells

Scientists found that SUMOylation of the M2 isoform of pyruvate kinase, a rate-limiting glycolytic enzyme catalyzing the dephosphorylation of phosphoenolpyruvate to pyruvate, is prevalent in a variety of leukemic cell lines as well as primary samples from patients with leukemia through multiple-reaction monitoring based targeted mass spectrometry analysis.
[Cell Death & Disease]
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Dynamic Immune Profiling Identifies the Stronger Graft-Versus-Leukemia (GVL) Effects With Haploidentical Allografts Compared to HLA-Matched Stem Cell Transplantation

Researchers employed two nonirradiated leukemia mouse models which carried human AML-ETO or MLL-AF9 fusion gene to establish haplo-identical and major histocompatibility-matched transplantation models and investigated the immune cell dynamic response during leukemia development in vivo.
[Cellular & Molecular Immunology]
Guo, H., Chang, Y.-J., Hong, Y., Xu, L.-P., Wang, Y., Zhang, X.-H., Wang, M., Chen, H., Chen, Y.-H., Wang, F.-R., Wei-Han, Sun, Y.-Q., Yan, C.-H., Tang, F.-F., Mo, X.-D., Liu, K.-Y., & Huang, X.-J. (2021). Dynamic immune profiling identifies the stronger graft-versus-leukemia (GVL) effects with haploidentical allografts compared to HLA-matched stem cell transplantation. Cellular & Molecular Immunology, 1–14. https://doi.org/10.1038/s41423-020-00597-1 Cite
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Overcoming Target Epitope Masking Resistance that Can Occur on Low-Antigen-Expresser AML Blasts after IL-1RAP Chimeric Antigen Receptor T Cell Therapy Using the Inducible Caspase 9 Suicide Gene Safety Switch

As acute myeloid leukemia (AML) primary blasts express different levels of accessory protein of the interleukin-1 receptor (IL-1RAP), scientists modeled transduction of different AML tumor cell lines screened for density of antigenic sites with their lentiviral vectors carrying a third-generation IL-1RAP chimeric antigen receptor, an iCASP9 suicide gene, and a truncated CD19 surface gene.
[Cancer Gene Therapy]
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Integrated Decoding Hematopoiesis and Leukemogenesis Using Single-Cell Sequencing and Its Medical Implication

Scientists analyzed ~200,000 single-cell transcriptomes of bone marrow mononuclear cells and its subsets from 23 clinical samples. They constructed a comprehensive cell atlas as hematopoietic reference.
[Cell Discovery]
Qin, P., Pang, Y., Hou, W., Fu, R., Zhang, Y., Wang, X., Meng, G., Liu, Q., Zhu, X., Hong, N., Cheng, T., & Jin, W. (2021). Integrated decoding hematopoiesis and leukemogenesis using single-cell sequencing and its medical implication. Cell Discovery, 7(1), 1–17. https://doi.org/10.1038/s41421-020-00223-4 Cite
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USP15 Deubiquitinase Safeguards Hematopoiesis and Genome Integrity in Hematopoietic Stem Cells and Leukemia Cells

The authors systematically inactivated deubiquitinating enzymes (DUBs) in mouse hematopoietic progenitors using in vivo small hairpin RNA (shRNA) screens. They found that multiple DUBs may be individually required for hematopoiesis and identify ubiquitin-specific protease 15 (USP15) as essential for hematopoietic stem cell maintenance in vitro and in transplantations and Usp15 knockout (KO) mice in vivo.
[Cell Reports]
USP15 Deubiquitinase Safeguards Hematopoiesis and Genome Integrity in Hematopoietic Stem Cells and Leukemia Cells: Cell Reports. (n.d.). Retrieved January 4, 2021, from https://www.cell.com/cell-reports/fulltext/S2211-1247(20)31522-9 Cite
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