Preleukemia and Leukemia-Initiating Cell Activity in inv(16) Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a collection of hematologic malignancies with specific driver mutations that direct the pathology of the disease. The understanding of the origin and function of these mutations at early stages of transformation is critical to understand the etiology of the disease and for the design of effective therapies. The chromosome inversion inv(16) is thought to arise as a founding mutation in a hematopoietic stem cell (HSC) to produce preleukemic HSCs (preL-HSCs) with myeloid bias and differentiation block, and predisposed to AML. Studies in mice and human AML cells have established that inv(16) AML follows a clonal evolution model, in which preL-HSCs expressing the fusion protein CBFβ–SMMHC persist asymptomatic in the bone marrow. The emerging leukemia-initiating cells (LICs) are composed by the inv(16) and a heterogeneous set of mutations. In this review, we will discuss the current understanding of inv(16) preleukemia development, and the function of CBFβ–SMMHC related to preleukemia progression and LIC activity. We also discuss important open mechanistic questions in the etiology of inv(16) AML

Core-binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis

Adenosine-to-inosine RNA editing, which is catalyzed by adenosine deaminases acting on RNA (ADAR) family of enzymes, ADAR1 and ADAR2, has been shown to contribute to multiple cancers. However, other than the chronic myeloid leukemia blast crisis, relatively little is known about its role in other types of hematological malignancies. Here, we found that ADAR2, but not ADAR1 and ADAR3, was specifically downregulated in the core-binding factor (CBF) acute myeloid leukemia (AML) with t(8;21) or inv(16) translocations. In t(8;21) AML, RUNX1-driven transcription of ADAR2 was repressed by the RUNX1-ETO additional exon 9a fusion protein in a dominant-negative manner. Further functional studies confirmed that ADAR2 could suppress leukemogenesis specifically in t(8;21) and inv16 AML cells dependent on its RNA editing capability. Expression of 2 exemplary ADAR2-regulated RNA editing targets coatomer subunit α and component of oligomeric Golgi complex 3 inhibits the clonogenic growth of human t(8;21) AML cells. Our findings support a hitherto, unappreciated mechanism leading to ADAR2 dysregulation in CBF AML and highlight the functional relevance of loss of ADAR2-mediated RNA editing to CBF AML.Published versionThis work was supported by the Singapore Ministry of Health’s National Medical Research Council (NMRC), the Singapore National Research Foundation, the Singapore Ministry of Education (MOE) under its Research Centres of Excellence initiative, and the National Institutes of Health with following details: Singapore Translational Research Investigator Award, National Institutes of Health grant (P01 HL131477 (D.G.T.), MOE Tier 2 grants (MOE2019 T2-1-083 and MOE2019 T2-2-008), NMRC Clinician Scientist-Individual Research grants (project IDs: MOH 000214 and MOH-001092-00), and the Health and Biomedical Sciences Industry Alignment Fund Pre-Positioning (H20C6a0034) (L.C.), NMRC Open Fund Young Individual Research grant ( MOH OFYIRG20nov-0011) and MOE Research Scholarship Block grant (N 171 000 019 001) (Q.Z.), as well as MOE Tier 3 grant (MOE2014-T3-1-006) (D.G.T. and L.C.)