Epigenetic Reprogramming and Emerging Epigenetic Therapies in CML

Abstract

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by BCR-ABL1, an oncogenic fusion gene arising from the Philadelphia chromosome. The development of tyrosine kinase inhibitors (TKIs) to overcome the constitutive tyrosine kinase activity of the BCR-ABL protein has dramatically improved disease management and patient outcomes over the past 20 years. However, the majority of patients are not cured and developing novel therapeutic strategies that target epigenetic processes are a promising avenue to improve cure rates. A number of epigenetic mechanisms are altered or reprogrammed during the development and progression of CML, resulting in alterations in histone modifications, DNA methylation and dysregulation of the transcriptional machinery. In this review these epigenetic alterations are examined and the potential of epigenetic therapies are discussed as a means of eradicating residual disease and offering a potential cure for CML in combination with current therapies.

Abrogation of histone deacetylases (HDACs) decreases survival of chronic myeloid leukemia cells: New insight into attenuating effects of the PI3K/c‐Myc axis on panobinostat cytotoxicity

“…Studies illustrated that BCR/ABL‐mediated alteration in histone and non‐histone proteins acetylation has a prominent effect in reprogramming epigenetic mechanisms in favor of cancer cells, resulting in both development and progression of CML (Bugler et al, 2019). Accordingly, it was reasonable to hypothesize that the simultaneous inhibition of HDACs and BCR/ABL could produce superior cytotoxicity in K562 cells.…”

Regulating Methylation at H3K27: A Trick or Treat for Cancer Cell Plasticity

“…In hematological malignancies, the role of EZH2 may be either oncogenic or tumor suppressive [ 102 , 103 ]. The over-expression of mutant EZH2 has been reported in a wide variety of B-and T-cell lymphoproliferative disorders [ 103 , 104 , 105 , 106 ].…”

“…While the reason for these conflicting results remains to be determined, some evidence shows that in adult HSCs, EZH1 can compensate for EZH2 loss, which can help to explain these discrepancies [ 108 ]. Although many studies use cell lines, primary cells and mouse models of CML have shown dysregulated expression, but no mutations in the PRC2 components [ 102 ]. In MDS and MDS-derived acute myeloid leukemia (AML), EZH2 over-expression is correlated with poor prognosis.…”

Mecanismos moleculares emergentes y células madre leucémicas en la quimiorresistencia de tumores hematológicos

“…La farmacocinética de los agentes quimioterapéuticos, es decir, su distribución en el organismo, mecanismo de acción o activación, así como la presencia de barreras fisiológicas como la infiltración del sistema nervioso central por células tumorales, pueden limitar la biodisponibilidad de los fármacos en el sitio activo del proceso tumoral. Este tipo de resistencia, conocido como resistencia farmacológica, puede ser modulada al ajustar la vía de administración, dosis o el esquema de administración del fármaco [11][12][13][14] .…”