BAALC-associated gene expression profiles define IGFBP7 as a novel molecular marker in acute leukemia.
Over expression of BAALC (brain and acute leukemia, cytoplasmic) predicts an inferior outcome in acute myeloid leukemia (AML) and acute lymphoblastic leukemia patients. To identify BAALC-associated genes that give insights into its functional role in chemotherapy resistance, gene expression signatures differentiating high from low BAALC expressers were generated from normal CD34(+) progenitors, T-acute lymphoblastic leukemia (T-ALL) and AML samples. The insulin-like growth factor binding protein 7 (IGFBP7) was one of the four genes (CD34, CD133, natriuretic peptide receptor C (NPR3), IGFBP7) coexpressed with BAALC and common to the three entities. In T-ALL, high IGFBP7-expression was associated with an immature phenotype of early T-ALL (P<0.001), expression of CD34 (P<0.001) and CD33 (P<0.001). Moreover, high IGFBP7-expression predicted primary therapy resistance (P=0.03) and inferior survival in T-ALL (P=0.03). In vitro studies revealed that IGFBP7 protein significantly inhibited the proliferation of leukemia cell lines (Jurkat cells: 42% reduction, P=0.002; KG1a cells: 65% reduction, P<0.001). In conclusion, IGFBP7 was identified as a BAALC coexpressed gene. Furthermore, high IGFBP7 was associated with stem cell features and treatment failure in T-ALL. In contrast to BAALC, which likely represents only a surrogate marker of treatment failure in acute leukemia, IGFBP7 regulates the proliferation of leukemic cells and might be involved in chemotherapy resistance.
Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Medizinische Klinik III, Berlin, Germany.
S
S
Heesch
C
C
Schlee
M
M
Neumann
A
A
Stroux
A
A
Kühnl
S
S
Schwartz
T
T
Haferlach
N
N
Goekbuget
D
D
Hoelzer
E
E
Thiel
W-K
WK
Hofmann
C D
CD
Baldus
D017209:Apoptosis; D001483:Base Sequence; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D017931:DNA Primers; D004261:DNA Replication; D020869:Gene Expression Profiling; D006801:Humans; D016130:Immunophenotyping; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics*; D015448:Leukemia, B-Cell / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*
C442828:BAALC protein, human; D014408:Biomarkers, Tumor; D017931:DNA Primers; D018969:Insulin-Like Growth Factor Binding Proteins; D009363:Neoplasm Proteins; C102529:insulin-like growth factor binding protein-related protein 1