Leukemia Stemness and Co-occurring Mutations Drive Resistance to IDH Inhibitors in Acute Myeloid Leukemia

Scientists performed multipronged genomic analyses in longitudinally collected specimens from 60 IDH1- or IDH2-mutant AML patients treated with the inhibitors.
[Nature Communications]
Wang, F., Morita, K., DiNardo, C. D., Furudate, K., Tanaka, T., Yan, Y., Patel, K. P., MacBeth, K. J., Wu, B., Liu, G., Frattini, M., Matthews, J. A., Little, L. D., Gumbs, C., Song, X., Zhang, J., Thompson, E. J., Kadia, T. M., Garcia-Manero, G., … Takahashi, K. (2021). Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia. Nature Communications, 12(1), 2607. https://doi.org/10.1038/s41467-021-22874-x Cite
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Targeting MicroRNA-Mediated Gene Repression Limits Adipogenic Conversion of Skeletal Muscle Mesenchymal Stromal Cells

Scientists uncovered a molecular fate switch, involving miR-206 and the transcription factor Runx1, that controls fibroadipogenic progenitor differentiation to adipocytes.
[Cell Stem Cell]
Wosczyna, M. N., Carbajal, E. E. P., Wagner, M. W., Paredes, S., Konishi, C. T., Liu, L., Wang, T. T., Walsh, R. A., Gan, Q., Morrissey, C. S., & Rando, T. A. (2021). Targeting microRNA-mediated gene repression limits adipogenic conversion of skeletal muscle mesenchymal stromal cells. Cell Stem Cell, 0(0). https://doi.org/10.1016/j.stem.2021.04.008 Cite
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Identification of Therapeutic Targets of the Hijacked Super-Enhancer Complex in EVI1-Rearranged Leukemia

The authors unraveled key components of G2DHE-bound transcription factors involved in the deregulation of EVI1.
[Leukemia]
Kiehlmeier, S., Rafiee, M.-R., Bakr, A., Mika, J., Kruse, S., Müller, J., Schweiggert, S., Herrmann, C., Sigismondo, G., Schmezer, P., Krijgsveld, J., & Gröschel, S. (2021). Identification of therapeutic targets of the hijacked super-enhancer complex in EVI1 -rearranged leukemia. Leukemia, 1–12. https://doi.org/10.1038/s41375-021-01235-z Cite
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iPSC Modeling of Stage-Specific Leukemogenesis Reveals BAALC as a Key Oncogene in Severe Congenital Neutropenia

Researchers established a model of stepwise leukemogenesis in congenital neutropenia (CN)/acute myeloid leukemiausing CRISPR-Cas9 gene editing of CN patient-derived iPSCs.
[Cell Stem Cell]
Dannenmann, B., Klimiankou, M., Oswald, B., Solovyeva, A., Mardan, J., Nasri, M., Ritter, M., Zahabi, A., Arreba-Tutusaus, P., Mir, P., Stein, F., Kandabarau, S., Lachmann, N., Moritz, T., Morishima, T., Konantz, M., Lengerke, C., Ripperger, T., Steinemann, D., … Skokowa, J. (2021). iPSC modeling of stage-specific leukemogenesis reveals BAALC as a key oncogene in severe congenital neutropenia. Cell Stem Cell, 0(0). https://doi.org/10.1016/j.stem.2021.03.023 Cite
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Nuclear IL-33 Plays an Important Role in the Suppression of Filaggrin, Loricrin, Keratin 1, and Keratin 10 by IL-4 and IL-13 in Human Keratinocytes

Researchers investigated whether intracellular IL-33 is involved in IL-4/IL-13 function. In monolayer-culture and living skin equivalent, IL-4/IL-13 increased the expression of full-length IL-33 in the nucleus of keratinocytes by activating the MEK/ERK signaling pathway, which is necessary for the inhibition of differentiation markers filaggrin, loricrin, keratin1, and keratin 10.
[Journal of Investigative Dermatology]
Dai, X., Utsunomiya, R., Shiraishi, K., Mori, H., Muto, J., Murakami, M., & Sayama, K. (2021). Nuclear IL-33 plays an important role in the suppression of filaggrin, loricrin, keratin 1, and keratin 10 by IL-4 and IL-13 in human keratinocytes. Journal of Investigative Dermatology, 0(0). https://doi.org/10.1016/j.jid.2021.04.002 Cite
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Plasmacytoid Dendritic Cell Expansion Defines a Distinct Subset of RUNX1-Mutated Acute Myeloid Leukemia

Investigators characterized patients with AML with plasmacytoid dendritic cells (pDC) expansion, which they observed in ∼5% of AML cases. pDC-AMLs often possessed cross-lineage antigen expression and have adverse risk stratification with poor outcome.
[Blood]
Xiao, W., Chan, A., Waarts, M. R., Mishra, T., Liu, Y., Cai, S. F., Yao, J., Gao, Q., Bowman, R. L., Koche, R. P., Csete, I. S., DelGaudio, N. L., Derkach, A., Baik, J., Yanis, S., Famulare, C. A., Patel, M., Arcila, M. E., Stahl, M., … Levine, R. L. (2021). Plasmacytoid dendritic cell expansion defines a distinct subset of RUNX1-mutated acute myeloid leukemia. Blood, 137(10), 1377–1391. https://doi.org/10.1182/blood.2020007897 Cite
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Genetics of Donor Cell Leukemia in Acute Myelogenous Leukemia and Myelodysplastic Syndrome

The authors describe the spectrum of genetic aberrations detected in DCL cases in the literature with regard to the character of the individual cases, existing family cohorts that carry individual genes, and functional studies that support etiologic roles in acute myelogenous leukemia development.
[Bone Marrow Transplantation]
Williams, L., Doucette, K., Karp, J. E., & Lai, C. (2021). Genetics of donor cell leukemia in acute myelogenous leukemia and myelodysplastic syndrome. Bone Marrow Transplantation, 1–15. https://doi.org/10.1038/s41409-021-01214-z Cite
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Generation of Reconstituted Hemato-Lymphoid Murine Embryos by Placental Transplantation into Embryos Lacking HSCs

Scientists established a procedure for placental HSC transplantation into E11.5 Runx1-deficient mice mated with G1-HRD-Runx1 transgenic mice that had no HSCs in the fetal liver.
[Scientific Reports]
Jeon, H., Asano, K., Wakimoto, A., Kulathunga, K., Tran, M. T. N., Nakamura, M., Yokomizo, T., Hamada, M., & Takahashi, S. (2021). Generation of reconstituted hemato-lymphoid murine embryos by placental transplantation into embryos lacking HSCs. Scientific Reports, 11(1), 4374. https://doi.org/10.1038/s41598-021-83652-9 Cite
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Mediator Subunit MED1 Is Required for E2A-PBX1–Mediated Oncogenic Transcription and Leukemic Cell Growth

The authors showed that Mediator interacted directly with E2A-PBX1 through an interaction of the MED1 subunit with an E2A activation domain. Results of MED1 depletion by CRISPR/Cas9 further indicated that MED1 was specifically required for E2A-PBX1–dependent gene activation and leukemic cell growth.
[Proceedings of the National Academy of Sciences of the United States of America]
Lee, Y.-L., Ito, K., Pi, W.-C., Lin, I.-H., Chu, C.-S., Malik, S., Cheng, I.-H., Chen, W.-Y., & Roeder, R. G. (2021). Mediator subunit MED1 is required for E2A-PBX1–mediated oncogenic transcription and leukemic cell growth. Proceedings of the National Academy of Sciences, 118(6). https://doi.org/10.1073/pnas.1922864118 Cite
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AIM2 in Regulatory T Cells Restrains Autoimmune Diseases

Scientists showed that the DNA-binding inflammasome receptor AIM2 had a T cell-intrinsic and inflammasome-independent role in the function of T regulatory cells.
[Nature]
Chou, W.-C., Guo, Z., Guo, H., Chen, L., Zhang, G., Liang, K., Xie, L., Tan, X., Gibson, S. A., Rampanelli, E., Wang, Y., Montgomery, S. A., Brickey, W. J., Deng, M., Freeman, L., Zhang, S., Su, M. A., Chen, X., Wan, Y. Y., & Ting, J. P.-Y. (2021). AIM2 in regulatory T cells restrains autoimmune diseases. Nature, 1–6. https://doi.org/10.1038/s41586-021-03231-w 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]
Xia, L., Jiang, Y., Zhang, X.-H., Wang, X.-R., Wei, R., Qin, K., & Lu, Y. (2021). SUMOylation disassembles the tetrameric pyruvate kinase M2 to block myeloid differentiation of leukemia cells. Cell Death & Disease, 12(1), 1–13. https://doi.org/10.1038/s41419-021-03400-9 Cite
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