Outcomes of Relapsed or Refractory Acute Myeloid Leukemia after Frontline Hypomethylating Agent and Venetoclax Regimens

Investigators found that patients failing front-line venetoclax + hypomethylating agents had high-risk biology, dismal overall survival despite salvage therapy, and new putative mechanisms of resistance.
[Haematologica]
Maiti, A., Rausch, C. R., Cortes, J. E., Pemmaraju, N., Daver, N. G., Ravandi, F., Garcia-Manero, G., Borthakur, G., Naqvi, K., Ohanian, M., Short, N. J., Alvarado, Y., Kadia, T. M., Takahashi, K., Yilmaz, M., Jain, N., Kornblau, S., Bravo, G. M., Sasaki, K., … Konopleva, M. Y. (2021). Outcomes of relapsed or refractory acute myeloid leukemia after frontline hypomethylating agent and venetoclax regimens. Haematologica, 106(3), 894–898. https://doi.org/10.3324/haematol.2020.252569 Cite
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Potential Targeting of FLT3 Acute Myeloid Leukemia

The authors review the rationale for targeting the FLT3 receptor in acute myeloid leukemia (AML), the impact of FLT3 mutation on patient prognosis, the current standard of care approaches to FLT3-mutated AML management, and the diverse array of FLT3 inhibitors in use and under investigation.
[Haematologica]
Ambinder, A. J., & Levis, M. (2021). Potential targeting of FLT3 acute myeloid leukemia. Haematologica, 106(3), 671–681. https://doi.org/10.3324/haematol.2019.240754 Cite
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Identification of Leukemic and Pre-leukemic Stem Cells by Clonal Tracking from Single-Cell Transcriptomics

Researchers demonstrated that leukemia stem cells, hematopoietic stem cells, and pre-leukemic stem cells could be identified and molecularly profiled by combining single-cell transcriptomics with lineage tracing using both nuclear and mitochondrial somatic variants.
[Nature Communications]
Velten, L., Story, B. A., Hernández-Malmierca, P., Raffel, S., Leonce, D. R., Milbank, J., Paulsen, M., Demir, A., Szu-Tu, C., Frömel, R., Lutz, C., Nowak, D., Jann, J.-C., Pabst, C., Boch, T., Hofmann, W.-K., Müller-Tidow, C., Trumpp, A., Haas, S., & Steinmetz, L. M. (2021). Identification of leukemic and pre-leukemic stem cells by clonal tracking from single-cell transcriptomics. Nature Communications, 12(1), 1366. https://doi.org/10.1038/s41467-021-21650-1 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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Identification of Gene Targets of Mutant C/EBPα Reveals a Critical Role for MSI2 in CEBPA-Mutated AML

Integrative analysis identified 117 p30-dependent REs associated with 33 strongly down-regulated genes upon p30-knockdown. CRISPR/Cas9-mediated mutational disruption of these genes revealed the RNA-binding protein MSI2 as a critical p30-target.
[Leukemia]
Heyes, E., Schmidt, L., Manhart, G., Eder, T., Proietti, L., & Grebien, F. (2021). Identification of gene targets of mutant C/EBPα reveals a critical role for MSI2 in CEBPA -mutated AML. Leukemia, 1–13. https://doi.org/10.1038/s41375-021-01169-6 Cite
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Mesenchymal Stem Cell Carriers Enhance Antitumor Efficacy Induced by Oncolytic Reovirus in Acute Myeloid Leukemia

Human umbilical cord mesenchymal stem cells were used to deliver reovirus using in vitro and in vivo models.
[International Immunopharmacology]
Wang, X., Yang, Y., Wang, N., Wu, X., Xu, J., Zhou, Y., Zhao, X., & He, Z. (2021). Mesenchymal stem cell carriers enhance antitumor efficacy induced by oncolytic reovirus in acute myeloid leukemia. International Immunopharmacology, 94, 107437. https://doi.org/10.1016/j.intimp.2021.107437 Cite
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Kmt2c Mutations Enhance HSC Self-Renewal Capacity and Convey a Selective Advantage after Chemotherapy

Scientists showed that KMT2C deletions conveyed a selective advantage to hematopoietic stem cells after chemotherapy treatment that may precipitate therapy-related myelodysplastic syndrome/acute myeloid leukemia.
[Cell Reports]
Chen, R., Okeyo-Owuor, T., Patel, R. M., Casey, E. B., Cluster, A. S., Yang, W., & Magee, J. A. (2021). Kmt2c mutations enhance HSC self-renewal capacity and convey a selective advantage after chemotherapy. Cell Reports, 34(7). https://doi.org/10.1016/j.celrep.2021.108751 Cite
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Abnormal Dopamine Receptor Signaling Allows Selective Therapeutic Targeting of Neoplastic Progenitors in AML Patients

The authors accessed patient cells from a Phase I dose escalation trial to resolve the cellular and molecular bases of response to thioridazine, and they extended these findings to an additional independent cohort of acute myeloid leukemia patient samples tested preclinically.
[Cell Reports Medicine]
Aslostovar, L., Boyd, A. L., Benoit, Y. D., Lu, J. D., Rodriguez, J. L. G., Nakanishi, M., Porras, D. P., Reid, J. C., Mitchell, R. R., Leber, B., Xenocostas, A., Foley, R., & Bhatia, M. (2021). Abnormal dopamine receptor signaling allows selective therapeutic targeting of neoplastic progenitors in AML patients. Cell Reports Medicine, 2(2). https://doi.org/10.1016/j.xcrm.2021.100202 Cite
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ORYZON Announces FDA Orphan Drug Designation Granted to iadademstat for Treatment of Acute Myeloid Leukemia

Oryzon Genomics, S.A. announced that the FDA has granted Orphan Drug Designation to the company’s first-in-class LSD1 inhibitor iadademstat for the treatment of patients with acute myeloid leukemia (AML).
[Oryzon Genomics, S.A.]
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Bluebird Bio Announces Temporary Suspension on Phase I/II and Phase III Studies of LentiGlobin Gene Therapy for Sickle Cell Disease (bb1111)

Bluebird Bio, Inc. announced that the company has placed its Phase I/II and Phase III studies of LentiGlobin gene therapy for sickle cell disease on a temporary suspension due to a reported Suspected Unexpected Serious Adverse Reaction of acute myeloid leukemia.
[bluebird bio, Inc. (BusinessWire, Inc.)]
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Sequential CRISPR Gene Editing in Human iPSCs Charts the Clonal Evolution of Myeloid Leukemia and Identifies Early Disease Targets

Scientists combined induced pluripotent stem cell and CRISPR-Cas9 technologies to develop a model of the clonal evolution of acute myeloid leukemia.
[Cell Stem Cell]
Wang, T., Pine, A. R., Kotini, A. G., Yuan, H., Zamparo, L., Starczynowski, D. T., Leslie, C., & Papapetrou, E. P. (2021). Sequential CRISPR gene editing in human iPSCs charts the clonal evolution of myeloid leukemia and identifies early disease targets. Cell Stem Cell. https://doi.org/10.1016/j.stem.2021.01.011 Cite
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