Abstract
Increased expression of c-MYC is observed in both Acute Myeloid Leukemia (AML) and T-cell Acute Lymphoblastic Leukemia (T-ALL). MYC binding protein 2 (MYCBP2) is a probable E3 ubiquitin ligase and its function in leukemia is unknown. IKZF1 deletion is associated with the development and poor outcome of ALL. Here, we observed significant high c-MYC expression and low MYCBP2 expression in adult ALL patients. Patients with high c-MYC expression and/or low MYCBP2 expression had higher WBC counts and a higher percentage of CD34+ or CD33+ cells, as well as splenomegaly, liver infiltration, higher BM blasts, and lower CR rate. Ikaros bound to the regulatory regions of c-MYC and MYCBP2, suppressed c-MYC and increased MYCBP2 expression in ALL cells. Expression of c-MYC mRNA was significantly higher in patients with IKZF1 deletion; conversely MYCBP2 mRNA expression was significantly lower in those patients. A CK2 inhibitor, which acts as an Ikaros activator, also suppressed c-MYC and increased MYCBP2 expression in an Ikaros (IKZF1) dependent manner in the ALL cells. In summary, our data indicated the correlation of high c-MYC expression, low MYCBP2 expression and high c-MYC plus low MYCBP2 expression with high-risk factors and proliferation markers in adult ALL patients. Our data also revealed an oncogenic role for an Ikaros/MYCBP2/c-MYC axis in adult ALL, providing a mechanism of target therapies that activate Ikaros in adult ALL.
Highlights
The MYC families of proteins are transcription factors with essential roles in cell growth and proliferation through their ability to regulate gene expression [1, 2]
We found that c-MYC expression is significantly higher in both B-acute lymphoblastic leukemia (ALL) and T- cell Acute Lymphoblastic Leukemia (T-ALL) patients compared to normal control (Fig. 1A)
Our findings indicate the significance of high c-MYC, low MYC binding protein 2 (MYCBP2) and low Ikaros expression in ALL patients, demonstrate c-MYC and MYCBP2 is the direct target of Ikaros and reveal a model for the oncogenic effect of an Ikaros/MYCBP2/c-MYC axis in adult ALL
Summary
The MYC families of proteins are transcription factors with essential roles in cell growth and proliferation through their ability to regulate gene expression [1, 2]. C-MYC is frequently activated in acute myeloid leukemia (AML), and plays an important role in the induction of leukemogenesis [3, 4]. C-MYC is frequently reported to be upregulated in acute lymphoblastic leukemia (ALL), the correlation of c-MYC expression with clinical features of ALL has not been fully described. It is reported that MYCBP2 is a candidate for the transformation-associated gene that maps to the 13q22.3 locus in Angioimmunoblastic T-cell lymphoma (AITL) [9]. Both the expression of MYCBP2 and its correlation with clinical features are unknown in ALL
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