Protein Kinase Gene Expression Profile in Adult Acute Lymphocytic Leukemia (ALL): Identification of Novel Therapeutic Targets.

Background. Despite the recent improvements in the treatment of acute lymphocytic leukemia (ALL), adults still have a poor outcome. The future of ALL management is likely to rely in the progressive introduction of novel targeted therapies. Protein kinase (PK) deregulation has been frequently observed in cancer; therefore, PK are regarded as attractive targets for anti-tumor therapies. The majority of PK inhibitors currently used in clinical trials in onco-hematology targets tyrosine kinases (TK) and receptor tyrosine kinases (RTK).

Methods. We evaluated the expression levels of PK genes in 133 adult ALL samples at the onset of the disease by oligonucleotide arrays (HGU133 Plus 2.0, Affymetrix). Leukemic cells from 91 samples were of B-cell origin and belonged to 4 molecular subgroups: BCR/ABL+ (40 pts), ALL1/AF4+ (5 pts), E2A/PBX+ (3 pts) and B-lineage ALL without known molecular abnormalities (43 pts), defined as B-NEG. The remaining 42 samples were of T-cell derivation. To compare the 5 ALL subgroups we performed an ANOVA analysis using a list of 1324 probesets coding for PK. The genes identified by ANOVA were further selected (mean expression values ≥300, fold change difference ≥1.5 in each group compared to every other group) to concentrate on distinguishing PK genes. This approach identified a set of distinctive PK for each ALL subgroup except for the B-NEG samples. To further investigate the B-NEG group we compared it with every other B-lineage ALL subset by t test using the aforementioned gene list and highlighted the genes that were overexpressed in this group when compared to at least two other subgroups.

Results. ANOVA identified 290 probesets differentially expressed among the 5 ALL subgroups. The selection criteria applied allowed to identify the PK genes distinctive of each group and to highlight those of particular interest, as TK and RTK. T-ALL and E2A/PBX+ ALL were characterized by the specific expression of 18 PK genes. T-ALL showed a high expression of ZAP-70, LCK, ITK, EPHB6, FGFR1 and RYK. MERTK, BLK, TNK2 were distinctive of the E2A/PBX+ group. Fifteen genes were specific of the ALL1/AF4+ samples: among these, FLT3, ILK and LTK were selected. Only 8 genes were specifically overexpressed in the BCR/ABL+ samples; apart from ABL, this group showed high expression levels of FYN. Although no PK was exclusively upregulated in the B-NEG cases, a consistent number of PK genes was overexpressed in these samples.

Conclusions. Our study indicates that each ALL subgroup shows a distinctive PK signature. The specific PK subsets identified include several TK and RTK genes - especially in T-ALL, and in the E2A/PBX+ and B-NEG groups - whose products may be suitable for targeted therapies. These results suggest that second generation TK inhibitors may be effective not only in BCR/ABL+ patients, but also in other ALL subsets, such as T-ALL, e2a/pbx+ and B-NEG ALL, and provide the rationale for testing the impact of currently available TK inhibitors in the management of adult ALL.