Starting with the first definition of epigenetics “to understand how the genotypes
of evolving organisms can respond to the environment in a more co‐ordinated fashion”
originated in the research of Conrad Hal Waddington (1942) until current days, the
field of epigenetics has evolved greatly (Dimopoulos and Gronbaek, 2019). We are now
aware not only of the substantial contribution of the epigenomic patterns in development
and homeostasis, but also of the profound implications of epigenetic alteration in
disease pathogenesis (Stahl et al., 2016). Hematological malignancies light the way
and provided proof-of-concept not only for the unraveling the role of epigenetic alterations
in disease, but also for correcting these alterations and the clinical development
of novel therapies (DNA hypomethylating agents and histone deacetylase inhibitors)
for patients with myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML).
Large scale studies of cancer cells show an epigenetic drift toward global hypomethylation
with enhances chromosomal instability or intensified hypermethylation at CpG islands
within the promoter of tumor suppressor genes and sustained tumorigenesis (Eden et
al., 2003; Herman and Baylin, 2003; Karpf and Matsui, 2005; Esteller, 2008). On top
of this, further research has shown that epigenetic mechanisms have deep implications
for the establishment of cancer permissive microenvironments (Maio et al., 2015).
The deploy of epigenetic alterations has been shown to hijack the mechanisms of immune
surveillance in order to escape the antitumor immune responses (Cao and Yan, 2020).
In this sense, by remodeling the tumor microenvironment, a combination between immunotherapy
and epigenetic agents may provide clinical benefit for patients with incomplete responses
to immunomodulatory agents (Villanueva et al., 2020). In addition, efforts are undertaken
to understand the role of epigenetic alterations and tumor microenvironment in reshaping
the metabolic fitness and chemoresistance of cancer cells (Carrer and Wellen, 2015;
Forte et al., 2019). There is increasing evidence that the tumor microenvironment
is essential for maintaining malignant hematopoiesis. Since stromal elements (i.e.,
cancer-associated fibroblast, endothelial cells and other) do not exhibit somatic
mutations, they are likely to be corrupted by the malignant cells via epigenetic driven
events (Sylvestre et al., 2020). To this point, mesenchymal stromal cells from AML
show focal points of DNA hypermethylation, but also global hypomethylation compared
to their normal counterparts (von der Heide et al., 2017). Therefore, epigenetic therapy
could benefit patients with hematological malignancies not only due to reprograming
the cancer cells, but also by rescuing the tumor microenvironment.
The Research Topic entitled Novel Drugs Targeting the Microenvironment and the Epigenetic
Changes in Hematopoietic Malignancies covers recent advancements in our understanding
of the role of the microenvironment in hematological malignancies. To this end, response
to epigenetic drugs are presented within a cohort of juvenile myelomonocytic leukemia
(JMML) cases that were molecularly annotated via targeted next generation sequencing
(NSG). Treatment with 5-Azacitydine was well tolerated and had effective results in
both de novo JMML and relapsed patients (Marcu et al., 2020). The authors are highlighting
the paramount role of microenvironment not only in disease progression and treatment
response, but also in the outcomes of bone marrow transplantation in these patients.
These data emphasize the importance of establishing a healthy substrate for normal
hematopoiesis in patients with MDS undergoing bone marrow transplantation. The article
is expending on the alterations that intervene in cancer associated stromal cells
and how different therapies, including epigenetic agents can modulate the malignant
environment (Teodorescu et al., 2020). The heterogeneity of the tumor microenvironment
within AML is discussed with a focus on how unique immune profiles can serve as a
surrogate distinct prognosis profiles for patients with hematological malignancies.
Whether or not these changes are related to genetic and epigenetic events remains
to be discussed (Antohe et al., 2020). The concept of minimal residual disease (MRD)
in oncological hematology is presented within this research topic (Radu et al., 2020).
In addition, DNA methylation patterns detected via revolutionary surface-enhanced
Raman spectroscopy (SERS) are used as quantifiable biomarkers of circulating tumor
cells in liquid biopsies (Turcas et al., 2020).
Although the critical influence of the epigenetic landscape on cancer cells survival
and development has been recognized, so is its role in the establishment of supportive
tumor environments. Nevertheless, the heterogeneous clinical response of hematological
malignancies patients to epigenetic therapy suggests a complex relation between epigenetics
and cellular behavior. Perhaps the newly emerging field of epitranscriptomis may provide
the missing link between modulation of gene expression and the malignant phenotype.
To this end, N6-methyladenosine (m6A) is the most common non-genetic alteration in
mRNAs. M6A impacts RNA metabolism and thus, mediates aberrant gene expression seen
in disease development (Chen et al., 2019). RNA methylation is mediated by m6A methyltransferases,
removed by demethylases and identified by m6A binding proteins, all of them recognized
as “writers,” “erasers,” and “readers” respectively (Lan et al., 2019). The mechanism
of RNA methylation in solid and hematological tumors is in its early years, without
comprehensive clarification, and whatever this mechanism can surpass epigenetic changes
is unknown. m6A enhances the translation of PTEN, BCL2, and c-MYC in AML (Vu et al.,
2017), where YTHDF2 (m6A binding proteins) increases the expression of Tal1 (Li et
al., 2018). On top, FMR1 (protein from the m6A binding complex) can bind multiple
mRNAs to impair their translation and function (Edupuganti et al., 2017). However,
how the entire RNA methylation machinery is functioning in cancer is still unknown;
available data are showing distinct expression profiles of various “writers,” “erasers”
and “readers” between cancer patients and distinct global m6A methylation profiles
(Chen et al., 2019). The heterogeneity of these molecular profiles is demonstrating
that RNA methylation is a dynamic process that can shift toward malignant favoring
mechanisms, including during epigenetic treatment. Therefore, hematological patients
that are non-responders to demethylating agents could be characterized by a dominant
RNA methylation profile that favors the cancer phenotype or could present compensatory
feedback mechanisms at the level of RNA to impede the modifications from the DNA induced
by epigenetic therapy. Wide screening of different markers from the RNA methylation
machinery could predict the eligible patients for epigenetic treatment, while analysis
of the molecular background of the non-responder patients could offer new insights
into the mechanisms of dynamic RNA methylation in cancer.
Author Contributions
All authors listed have made a substantial, direct, and intellectual contribution
to the work and approved it for publication.
Funding
DG and CT are supported by 3 grants from the Romanian Ministry of Research and Innovation:
Postdoctoral Research Projects 2020–2022 ‐ grant number PN-III-P1-1.1-PD-2019-0805,
contract number PD 122/2020); CCCDI-UEFISCDI, Project No. PN-III-P4-ID-PCCF-2016-0112
within PNCDI III, as well as by awarded for Young Research Teams 2020-2022 (Grant
No. PN-III-P1-1.1-TE-2019-0271), as well as by an international collaborative grant
of the European Economic Space between Romania and Iceland 2020-2022 (Grant No. 19-COP-0031).
GG is funded by K08 HL127269 (GG), R03 HL145226 (GG), P01CA225618 (GG), and P30 CA006973.
LQ is funded by a grant from the National Natural Science Foundation of China (Grant
No. 81800180) and the National Young Elite Scientists Sponsorship Program by the China
Association for Science and Technology (Grant No. 17-JCJQ-QT-032).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.