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Editorials
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Standing at odds: mutated RAS and hematopoietic stem cells
Monica Nafria and Constanze Bonifer
Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham, UK E-mail: CONSTANZE BONIFER - c.bonifer@bham.ac.uk
doi:10.3324/haematol.2019.230029
Acute myeloid leukemia (AML) is the most com- mon acute leukemia in adults and is characterized by the accumulation of myeloid leukemic blasts unable to complete differentiation. However, AML is a complex disease with variable outcomes and prognoses.1 Underlying these heterogeneous phenotypes is the fact that each sub-type of AML is defined by a different set of mutations and is controlled by a specific transcriptional and signaling network distinct to that of normal stem and progenitor cells.2 Genes mutated in AML are involved in gene regulation and include transcription factors, chro- matin modifiers / remodelers, splicing regulators, DNA methyltransferases and signaling regulators that control the activity of inducible transcription factors. The result is a profound deviation from the normal differentiation trajectory, with each AML sub-type taking a different path and establishing its own cellular identity.2,3 Most AML sub-types carry more than one mutation and, with the exception of MLL-translocations (which are a hall- mark of pediatric AML4), for a number of sub-types it has been shown that the first oncogenic hit is not sufficient to cause overt leukemia. In AML patients, mutations in genes from different functional categories co-exist, and data from sequencing studies as well as mouse models support this notion.5,6
The t(8;21) translocation, occurring in 7% of adult de novo patients, is one of the most frequent cytogenetic
aberrations in AML.7 This translocation fuses the DNA- binding domain coding region of the hematopoietic mas- ter regulator RUNX1 (AML1) to the Eight-twenty-One (ETO, RUNX1T1 or MTG8) gene, which encodes a nuclear co-repressor. The result is the formation of the AML1-ETO (alternatively named RUNX1-ETO) chimeric protein, which retains the ability to bind to RUNX1 bind- ing motifs but lacks the transactivation domain of RUNX1.8,9 Germline expression of full-length AML1-ETO in mice causes embryonic lethality,10,11 but conditional expression in hematopoietic stem cells (HSC) leads to an initial expansion of myeloid progenitor cells, including HSC and granulocyte-macrophage progenitors (GMP). Such expansion was also seen with AML1-ETO-trans- duced human cord blood-derived HSC in vitro.12 Fusion t(8;21) transcripts have been detected in utero and in post- natal blood samples13 and remain expressed at low levels in blood samples from t(8;21) AML patients in long-term remission.14 Furthermore, several AML1-ETO-expressing mouse models have failed to fully develop t(8;21) AML unless challenged by mutagenesis or aging,15-18 indicating the necessity of additional secondary mutations. These findings suggest that this chromosomal rearrangement is the driver mutation establishing a pre-leukemic clone. This notion is supported by the finding that t(8;21) patients present with a number of different secondary mutations.19 The most prominent of these mutations
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