Gene expression profiles associated with pediatric relapsed AML

Abstract

Development of relapse remains a problem for further improvements in the survival of pediatric AML patients. While virtually all patients show a good response to initial treatment, more patients respond poorly when treated at relapse. The cellular characteristics of leukemic blast cells that allow survival of initial treatment, relapse development and subsequent resistance to salvage treatment remain largely elusive. Therefore, we studied if leukemic blasts at relapse biologically resemble their initial diagnosis counterparts. We performed microarray gene expression profiling on paired initial and relapse samples of 23 pediatric AML patients. In 11 out of 23 patients, gene expression profiles of initial and corresponding relapse samples end up in different clusters in unsupervised analysis, indicating altered gene expression profiles. In addition, shifts in type I/II mutational status were found in 5 of these 11 patients, while shifts were found in 3 of the remaining 12 patients. Although differentially expressed genes varied between patients, they were commonly related to hematopoietic differentiation, encompassed genes involved in chromatin remodeling and showed associations with similar transcription factors. The top five were CEBPA, GFI1, SATB1, KLF2 and TBP. In conclusion, the leukemic blasts at relapse are biologically different from their diagnosis counterparts. These differences may be exploited for further development of novel treatment strategies.

Fig 1. Hierarchical clustering dendrogram of paired initial and relapse AML samples.

Similarity of GEP: Black bars indicate paired samples with GEP that correlate according to hierarchical cluster analysis. Grey bars indicate paired samples with mutational shifts between initial and relapse AML samples.

Fig 2. Heat map of probe-sets that distinguish initial from relapse AML samples.

The black top bar indicates initial AML samples and the top gray bar represents relapse AML samples.

Fig 3. TLE4, MALAT1, NUMB, EIF4E3 and HIST1H1C relative mRNA gene expression levels in an independent set of 7 paired diagnosis and relapse samples.

Fig 4. Transcription network visualization plot for patient 3.

Transcription network plot showing transcription factors (outer ring/ inner ring) that are predicted responsible for differential expression of shown target molecules (middle ring) between diagnosis and relapse of patient 3. A few transcription factors (CEBPA, GFI1, SATB1 and TBP) are responsible for the major changes in the differentially expressed target molecules.