Histone Modification Patterns Using RPPA-Based Profiling Predict Outcome in Acute Myeloid Leukemia Patients.

Abstract

Posttranslational histone tail modifications are known to play a role in leukemogenesis and are therapeutic targets. A global analysis of the level and patterns of expression of multiple histone-modifying proteins (HMP) in acute myeloid leukemia (AML) and the effect of different patterns of expression on outcome and prognosis has not been investigated in AML patients. Here we analyzed 20 HMP by reverse phase protein array (RPPA) in a cohort of 205 newly diagnosed AML patients. Protein levels were correlated with patient and disease characteristics, including survival and mutational state. We identified different protein clusters characterized by higher (more on) or lower (more off) expression of HMP, relative to normal CD34+ cells. On state of HMP was associated with poorer outcome compared to normal-like and a more off state. FLT3 mutated AML patients were significantly overrepresented in the more on state. DNA methylation related mutations showed no correlation with the different HMP states. In this study, we demonstrate for the first time that HMP form recurrent patterns of expression and that these significantly correlate with survival in newly diagnosed AML patients.