Getting to the core of ADAR2 activity in AML

In an insightful article in this issue of Blood, Guo et al¹ identify the RNA editing enzyme ADAR2 (adenosine deaminase acting on RNA2) as a core tumor suppressor in core binding factor acute myeloid leukemia (CBF AML).¹ The ADAR family of RNA editases includes (1) ADAR1, which exists as a constitutively active ADAR1p110 isoform and an inflammatory cytokine-inducible ADAR1p150 isoform, which is commonly deregulated in advanced malignancies; (2) ADAR2, which is primarily expressed in the brain; and (3) ADAR3, which is catalytically inactive and thought to function as an ADAR2 antagonist.² Over the last decade, cumulative studies have shown that epitranscriptomic disruption of RNA integrity by ADAR1 fuels therapeutic resistance in a broad array of malignancies, including hematologic malignancies like acute myeloid leukemia (AML).^2-7 Although ADAR1 is essential for the maintenance of normal adult hematopoiesis⁸ and transcriptomic integrity,⁹ deregulation of adenosine-to-inosine RNA editing by ADAR1 has been linked to malignant reprogramming of progenitors in hematopoietic malignancies.^2-5 Moreover, inflammatory cytokine-mediated ADAR1 activation in tumor microenvironments has been linked to immune silencing and immune checkpoint inhibitor resistance.^6,7 Conversely, relatively little is known about deregulation of ADAR2 in therapy-resistant malignancies like AML.

Although patients with CBF (core binding factor) AML are initially sensitive to cytarabine chemotherapy, they have a relatively high rate of chemotherapeutic resistance after relapse, resulting in a median overall survival rate of only 5 years.¹⁰ Specifically, CBF AML represents ∼10% of all AML cases and is typified by t(8;21) (q22;q22) or inv(16) (p13q22)/t(16;16) translocations that generate RUNX1/RUNX1T1 (AML1/ETO) and CBFB/MYH11 fusion genes, respectively.¹⁰ Moreover, AML1/ETO displaces c-Jun from PU.1, thereby inducing a myeloid maturation arrest that, with additional genetic and/or epigenetic changes, promotes leukemic transformation.¹⁰ Patients with CBF AML have a relatively low mutational burden compared with patients with intermediate or high-risk AML, which suggests that epigenetic (eg, TET2, ASXL1, and ASXL2) or epitranscriptomic (posttranscriptional) alterations may be important contributors to therapeutic resistance and relapse.

In this groundbreaking study, Guo et al demonstrate that ADAR2 deregulation is a key driver of CBF AML propagation.¹ In mouse models of t(8;21) CBF AML, RUNX1-driven transcription of ADAR2 was found to be repressed by the RUNX1-ETO AE9a fusion protein. Moreover, this dominant negative repression of ADAR2 could be reversed by overexpression of catalytically-active ADAR2 in both t(8;21) and inv16 AML cells. Furthermore, expression of COPA and COG3 ADAR2 RNA editing targets inhibited human t(8;21) AML cell line clonogenicity. As an important epitranscriptomic (posttranscriptional) process, RNA editing is usually regulated by inflammatory cytokine signaling. Thus, the role of the leukemia stem cell (LSC) niche in driving ADAR2 deregulation will need to be examined in murine models of CBF AML as well as in humanized LSC mouse models. Primate-specific Alu sequences represent key editing sites and therefore ADAR2-related editome analyses will need to be analyzed in human CBF AML samples and with lentiviral ADAR2 overexpression and short hairpin RNA (shRNA) knockdown studies. The role of ADAR2 in normal human hematopoietic stem and progenitor cell (HSPC) maintenance will also need to be investigated. Overall, this study provides novel mechanistic insights into the tumor-suppressive role of ADAR2-mediated RNA editing in CBF AML and sets the stage for investigating the cell type and tumor microenvironment specific roles of ADAR2 deaminase deregulation in human LSC propagation. Finally, the restoration of ADAR2-mediated tumor-suppressive activity may represent a core strategy for the development of therapies that effectively prevent CBF AML relapse.

Conflict-of-interest disclosure: C.J. is the cofounder of Aspera Biomedicines and Impact Biomedicines and receives royalties for patents related to CD47. K.S. declares no competing financial interests.