期刊
BLOOD CANCER JOURNAL
卷 11, 期 12, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41408-021-00584-3
关键词
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资金
- Leukemia Lymphoma Society of Canada
- Canadian Institutes of Health Research
- Clinician Investigator Program of the University of British Columbia [202002LFC-439884]
- Terry Fox Research Institute
- Canadian Cancer Society Research Institute
- Genome BC
- Genome Canada
- Leukemia and Lymphoma Society of Canada
- BC Cancer Foundation through the Leukemia and Myeloma Program
- BC Cancer Foundation John Auston Clinical Scientist Award
Blocked cellular differentiation is a key pathological feature in myeloid malignancies, with new therapies targeting differentiation pathways showing promise in clinical practice. In addition to promoting differentiation, the impact of inflammation and aging on therapeutic outcomes is also significant in these diseases.
Blocked cellular differentiation is a central pathologic feature of the myeloid malignancies, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Treatment regimens promoting differentiation have resulted in incredible cure rates in certain AML subtypes, such as acute promyelocytic leukemia. Over the past several years, we have seen many new therapies for MDS/AML enter clinical practice, including epigenetic therapies (e.g., 5-azacitidine), isocitrate dehydrogenase (IDH) inhibitors, fms-like kinase 3 (FLT3) inhibitors, and lenalidomide for deletion 5q (del5q) MDS. Despite not being developed with the intent of manipulating differentiation, induction of differentiation is a major mechanism by which several of these novel agents function. In this review, we examine the new therapeutic landscape for these diseases, focusing on the role of hematopoietic differentiation and the impact of inflammation and aging. We review how current therapies in MDS/AML promote differentiation as a part of their therapeutic effect, and the cellular mechanisms by which this occurs. We then outline potential novel avenues to achieve differentiation in the myeloid malignancies for therapeutic purposes. This emerging body of knowledge about the importance of relieving differentiation blockade with anti-neoplastic therapies is important to understand how current novel agents function and may open avenues to developing new treatments that explicitly target cellular differentiation. Moving beyond cytotoxic agents has the potential to open new and unexpected avenues in the treatment of myeloid malignancies, hopefully providing more efficacy with reduced toxicity.
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