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The role of epigenetic dysregulation in multiple myeloma

In multiple myeloma, genetic abnormalities may only provide half the story on disease progression1-3

Genetic abnormalities may only explain relapsed and relapsed and refractory multiple myeloma in <50% of patients.1-3 Epigenetic changes are defined as heritable changes in gene expression that are not due to any alteration in DNA sequence.4 In recent years, considerable evidence has shown that epigenetic dysregulation plays a critical role in the onset (early stage tumours) and progression of cancer.4

Epigenetic dysregulation in multiple myeloma

Modifications and structural configurations that occur within the DNA and chromatin structure of the myeloma cell, such as histone deacetylase (HDAC) overexpression, can affect the accessibility of DNA for transcription, which affects gene expression.4 HDAC overexpression causes hypoacetylation, a form of epigenetic dysregulation, which causes tumour suppressor genes to be silenced, or turned off. When tumour suppressor genes are silenced, they cause malignant cell growth and unregulated cellular proliferation.4-6

 

Epigenetic dysregulation may4:

Cancer cells are able to cause substantial epigenetic modifications, including HDAC overexpression. So, there is a need to create agents that can exert epigenetic effects, including HDAC inhibitors, to combat therapy-resistant progressive cancers, such as multiple myeloma.7

Most current therapies in multiple myeloma do not address the role epigenetic dysregulation plays in disease progression4-6

References:

  1. Rajkumar SV, Fonseca R, Dewald GW, et al. Cytogenetic abnormalities correlate with the plasma cell labeling index and extent of bone marrow involvement in myeloma. Cancer Genet Cytogenet. 1999;113(1):73-77.
  2. Abdi J, Chen G, Chang H. Drug resistance in multiple myeloma: latest findings and new concepts on molecular mechanisms. Oncotarget. 2013;4(12):2186-2207.
  3. Dimopoulos K, Gimsing P, Grønbæk K. The role of epigenetics in the biology of multiple myeloma. Blood Cancer J. 2014;4:e207.
  4. Atadja P. Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett. 2009;280(2):233-241.
  5. Zhu YX, Kortuem KM, Stewart AK. Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide, and pomalidomide in multiple myeloma. Leuk Lymphoma. 2013;54(4):683-687.
  6. Ocio EM, Vilanova D, Atadja P, et al. In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma. Haematologica. 2010;95(5):794-803.
  7. Cea M, Cagnetta A, Gobbi M, et al. New insights into the treatment of multiple myeloma with histone deacetylase inhibitors. Curr Pharm Des. 2013;19(4):734-744.