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Acute Myeloid Leukemia
Cell-intrinsic depletion of Aml1-ETO-expressing pre-leukemic hematopoietic stem cells
by K-Ras activating mutation
Cristina Di Genua,1 Ruggiero Norfo,1 Alba Rodriguez-Meira,1 Wei Xiong Wen,1,2 Roy Drissen,1 Christopher A.G. Booth,1 Benjamin Povinelli,1 Emmanouela Repapi,3 Nicki Gray,3 Joana Carrelha,1 Laura M. Kettyle,1 Lauren Jamieson,1 Wen Hao Neo,1 Supat Thongjuea,1,2 Claus Nerlov,1 and Adam J. Mead1
ABSTRACT
Somatic mutations in acute myeloid leukemia are acquired sequentially and hierarchically. First, pre-leukemic mutations, such as t(8;21) that encodes AML1-ETO, are acquired within the hematopoietic stem cell (HSC) compartment, while signaling pathway mutations, including KRAS activating mutations, are late events acquired during transformation of leukemic progenitor cells and are rarely detectable in HSC. This raises the possibility that signaling pathway mutations are detrimental to clonal expansion of pre-leukemic HSC. To address this hypothesis, we used con- ditional genetics to introduce Aml1-ETO and K-RasG12D into murine HSC, either individually or in combination. In the absence of activated Ras, Aml1-ETO-expressing HSC conferred a competitive advantage. However, activated K-Ras had a marked detrimental effect on Aml1-ETO-expressing HSC, leading to loss of both phenotypic and functional HSC. Cell cycle analysis revealed a loss of quiescence in HSC co-expressing Aml1-ETO and K-RasG12D, accompanied by an enrichment in E2F and Myc target gene expression and depletion of HSC self-renewal-associated gene expression. These findings provide a mechanistic basis for the observed absence of KRAS signaling mutations in the pre-malignant HSC compartment.
Introduction
Acute myeloid leukemia (AML) is a poor prognosis hematopoietic malignancy caused by the uncontrolled proliferation of differentiation-arrested myeloid cells.1,2 Genome sequencing studies have comprehensively characterized the mutational landscape of AML, identifying many somatically acquired recurrent driver muta- tions.3 Whist AML is a genetically complex disease, a number of general principles underlie the clonal evolution in AML. Genes mutated in AML can be classified into distinct categories such as chromatin modifiers, transcription factor fusions, and signal transduction genes,3 with most patients showing co-mutation of genes with- in at least two of these functional groups. Genomic data from sequencing studies, together with mechanistic studies using mouse models,4-6 support the concept that certain classes of mutation frequently co-occur during leukemia development, whereas mutations of the same functional group are often mutually exclusive.7
Acute myeloid leukemia has long been recognized as a hierarchically organized, stem cell-propagated disease.8 However, more recently, analysis of purified hematopoietic stem cells (HSC) and progenitor populations from AML patients have revealed that leukemia-initiating mutations, which include balanced translo- cations and mutations in epigenetic regulators, are frequently acquired within the HSC compartment as early events in disease evolution, generating so called “pre- leukemic” stem cells.9-12 In particular, the t(8;21) translocation, which generates the fusion protein AML1-ETO (also known as RUNX1-RUNX1T1 and AML1-MTG8) occurs in approximately 7% of adult AML patients.13 Several lines of evidence sug-
Ferrata Storti Foundation
Haematologica 2019 Volume 104(11):2215-2224
1MRC Molecular Haematology Unit; 2WIMM Centre for Computational Biology and 3Computational Biology Research Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
CN and AJM contributed equally to this work.
Correspondence:
ADAM J. MEAD
adam.mead@imm.ox.ac.uk
CLAUS NERLOV
claus.nerlov@imm.ox.ac.uk
Received: September 19, 2018. Accepted: April 9, 2019. Pre-published: May 10, 2019.
doi:10.3324/haematol.2018.205351
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/11/2215
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