title: Gene expression profiling of minimally differentiated acute myeloid leukemia: M0 is a distinct entity subdivided by RUNX1 mutation status.
abstract: Minimally differentiated acute myeloid leukemia (AML-M0) is defined by immature morphology and expression of early hematologic markers. By gene expression profiling (GEP) and subsequent unsupervised analysis of 35 AML-M0 samples and 253 previously reported AML cases, we demonstrate that AML-M0 cases express a unique signature that is largely separated from other molecular subtypes. Hematologic transcription regulators such as CEBPA, CEBPD, and ETV6, and the differentiation associated gene MPO appeared strongly down-regulated, in line with the primitive state of this leukemia. AML-M0 frequently carries loss-of-function RUNX1 mutation. Unsupervised analyses revealed a subdivision between AML-M0 cases with and without RUNX1 mutations. RUNX1 mutant AML-M0 samples showed a distinct up-regulation of B cell-related genes such as members of the B-cell receptor complex, transcription regulators RUNX3, ETS2, IRF8, or PRDM1, and major histocompatibility complex class II genes. Importantly, prediction with high accuracy of the AML-M0 subtype and prediction of patients carrying RUNX1 mutation within this subtype were possible based on the expression level of only a few transcripts. We propose that RUNX1 mutations in this AML subgroup cause lineage infidelity, leading to aberrant coexpression of myeloid and B-lymphoid genes. Furthermore, our results imply that AML-M0, although originally determined by morphology, constitutes a leukemia subgroup.
authors: Department of Toxicogenetics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Fernando P G
authors: FP
authors: Silva
authors: Sigrid M A
authors: SM
authors: Swagemakers
authors: Claudia
authors: C
authors: Erpelinck-Verschueren
authors: Bas J
authors: BJ
authors: Wouters
authors: Ruud
authors: R
authors: Delwel
authors: Harry
authors: H
authors: Vrieling
authors: Peter
authors: P
authors: van der Spek
authors: Peter J M
authors: PJ
authors: Valk
authors: Micheline
authors: M
authors: Giphart-Gassler
mesh_terms: D001402:B-Lymphocytes / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics*; D002454:Cell Differentiation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D053263:Gene Regulatory Networks; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D050676:Core Binding Factor Alpha 2 Subunit; C493728:RUNX1 protein, human