Gene expression profiling of minimally differentiated acute myeloid leukemia: M0 is a distinct entity subdivided by RUNX1 mutation status.

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.