Acute myeloid leukemia: current progress and future directions

Kantarjian, Hagop M.; Kadia, Tapan M.; DiNardo, Courtney D.; Daver, Naval; Borthakur, Gautam; Garcia‐Manero, Guillermo; Konopleva, Marina; Ravandi, Farhad

doi:10.1038/s41408-021-00425-3

Cited by 427 publications

(362 citation statements)

References 178 publications

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“…AML is a heterogeneous disease with poor survival and a high relapse rate. With advances in understanding the pathogenesis of AML, novel potential therapies for AML, including the refinement of conventional cytotoxic chemotherapies, genetic and epigenetic targeted drugs, and immunotherapies, have been developed in recent years [ 17 , 18 , 19 ]. However, the treatment of AML with DNMT3A mutations still faces challenges.…”

Section: Introductionmentioning

confidence: 99%

DNMT3A Mutation-Induced CDK1 Overexpression Promotes Leukemogenesis by Modulating the Interaction between EZH2 and DNMT3A

et al. 2021

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DNMT3A mutations are frequently identified in acute myeloid leukemia (AML) and indicate poor prognosis. Previously, we found that the hotspot mutation DNMT3A R882H could upregulate CDK1 and induce AML in conditional knock-in mice. However, the mechanism by which CDK1 is involved in leukemogenesis of DNMT3A mutation-related AML, and whether CDK1 could be a therapeutic target, remains unclear. In this study, using fluorescence resonance energy transfer and immunoprecipitation analysis, we discovered that increased CDK1 could compete with EZH2 to bind to the PHD-like motif of DNMT3A, which may disturb the protein interaction between EZH2 and DNMT3A. Knockdown of CDK1 in OCI-AML3 cells with DNMT3A mutation markedly inhibited proliferation and induced apoptosis. CDK1 selective inhibitor CGP74514A (CGP) and the pan-CDK inhibitor flavopiridol (FLA) arrested OCI-AML3 cells in the G2/M phase, and induced cell apoptosis. CGP significantly increased CD163-positive cells. Moreover, the combined application of CDK1 inhibitor and traditional chemotherapy drugs synergistically inhibited proliferation and induced apoptosis of OCI-AML3 cells. In conclusion, this study highlights CDK1 overexpression as a pathogenic factor and a potential therapeutic target for DNMT3A mutation-related AML.

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Section: Introductionmentioning

confidence: 99%

DNMT3A Mutation-Induced CDK1 Overexpression Promotes Leukemogenesis by Modulating the Interaction between EZH2 and DNMT3A

et al. 2021

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“…The disease phenotype and its clinical course are strikingly influenced by several recurrent mutations, which define the prognostic stratification of patients. Some recurrently mutated genes are now potential targets for a series of newly approved or investigational treatments [4][5][6]. Since 1970, the standard of care for AML patients has been based on chemotherapeutic treatment (the '3 + 7' regimen, combining daunorubicin and cytarabine), resulting in 5-year survival rates of 40-45% for patients up to 55 years, that decrease to 30-35% for patients up to 60 and may become as low as 10-15% in older patients [7,8].…”

Section: Introductionmentioning

confidence: 99%

The Role of Hypoxic Bone Marrow Microenvironment in Acute Myeloid Leukemia and Future Therapeutic Opportunities

Bruno

Mancini

Santis

et al. 2021

IJMS

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Acute myeloid leukemia (AML) is a hematologic malignancy caused by a wide range of alterations responsible for a high grade of heterogeneity among patients. Several studies have demonstrated that the hypoxic bone marrow microenvironment (BMM) plays a crucial role in AML pathogenesis and therapy response. This review article summarizes the current literature regarding the effects of the dynamic crosstalk between leukemic stem cells (LSCs) and hypoxic BMM. The interaction between LSCs and hypoxic BMM regulates fundamental cell fate decisions, including survival, self-renewal, and proliferation capacity as a consequence of genetic, transcriptional, and metabolic adaptation of LSCs mediated by hypoxia-inducible factors (HIFs). HIF-1α and some of their targets have been associated with poor prognosis in AML. It has been demonstrated that the hypoxic BMM creates a protective niche that mediates resistance to therapy. Therefore, we also highlight how hypoxia hallmarks might be targeted in the future to hit the leukemic population to improve AML patient outcomes.

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“…Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and represents another disease setting in which CAR-T and CAR-NK cells may help improve patient outcomes [ 9 ]. AML is a biologically and molecularly heterogenous group of diseases and the long-term survival rate for most patients remains poor despite many efforts, including precision medicine approaches designed to target specific cellular pathways known to be dysregulated in leukemia cells [ 10 , 11 ]. The observation that, as compared to healthy hematopoietic cells, AML cells express higher levels of the surface antigen CD123 (the IL-3 receptor subunit alpha) makes this an interesting target for therapy [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Improved Activity against Acute Myeloid Leukemia with Chimeric Antigen Receptor (CAR)-NK-92 Cells Designed to Target CD123

Morgan

Kloos

Lenz

et al. 2021

Viruses

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Anti-cancer activity can be improved by engineering immune cells to express chimeric antigen receptors (CARs) that recognize tumor-associated antigens. Retroviral vector gene transfer strategies allow stable and durable transgene expression. Here, we used alpharetroviral vectors to modify NK-92 cells, a natural killer cell line, with a third-generation CAR designed to target the IL-3 receptor subunit alpha (CD123), which is strongly expressed on the surface of acute myeloid leukemia (AML) cells. Alpharetroviral vectors also contained a transgene cassette to allow constitutive expression of human IL-15 for increased NK cell persistence in vivo. The anti-AML activity of CAR-NK-92 cells was tested via in vitro cytotoxicity assays with the CD123+ AML cell line KG-1a and in vivo in a patient-derived xenotransplantation CD123+ AML model. Unmodified NK-92 cells or NK-92 cells modified with a truncated version of the CAR that lacked the signaling domain served as controls. Alpharetroviral vector-modified NK-92 cells stably expressed the transgenes and secreted IL-15. Anti-CD123-CAR-NK-92 cells exhibited enhanced anti-AML activity in vitro and in vivo as compared to control NK-92 cells. Our data (1) shows the importance of IL-15 expression for in vivo persistence of NK-92 cells, (2) supports continued investigation of anti-CD123-CAR-NK cells to target AML, and (3) points towards potential strategies to further improve CAR-NK anti-AML activity.

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Acute myeloid leukemia: current progress and future directions

Cited by 427 publications

References 178 publications

DNMT3A Mutation-Induced CDK1 Overexpression Promotes Leukemogenesis by Modulating the Interaction between EZH2 and DNMT3A

DNMT3A Mutation-Induced CDK1 Overexpression Promotes Leukemogenesis by Modulating the Interaction between EZH2 and DNMT3A

The Role of Hypoxic Bone Marrow Microenvironment in Acute Myeloid Leukemia and Future Therapeutic Opportunities

Improved Activity against Acute Myeloid Leukemia with Chimeric Antigen Receptor (CAR)-NK-92 Cells Designed to Target CD123

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