Insulin-like Growth Factor Binding Protein 7 Activates the Retinoid Acid Differentiation Pathway in Acute Myeloid Leukemia Cells

• Published in: Blood 2018-11, Vol.132 (Supplement 1), p.3937-3937
• Main Authors: Van Gils, Noortje, Verhagen, Han J.M.P., Rutten, Arjo, Menezes, Renee X., Tsui, Mei-Ling, Dekens, Esmee, Denkers, Fedor, Vermue, E, Janssen, Jeroen J. W.M., Ossenkoppele, Gert J., Smit, Linda
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2018-99-115858

Acute myeloid leukemia (AML) is characterized by the accumulation of malignant blasts with impaired transcriptional differentiation programs. Despite important advances in AML therapy, the five-year overall survival rate of AML patients remains a disappointing 30-40%. This poor prognosis is mainly caused by survival of chemotherapy resistant leukemic cells, named leukemic stem cells (LSC), re-initiating relapse. However, for AML patients with PML-RARA positive acute promyelocytic leukemia (APL), treatment with all trans retinoic acid (ATRA) results in cure rates of >90%. Upon ATRA treatment, APL cells can restore transcription leading to granulocytic differentiation, and in combination with arsenic trioxide APL cells go into apoptosis. While the success of ATRA treatment has been demonstrated for APL patients, so far it has not proved effective for non-APL AML patients. Previously, we demonstrated that insulin-like growth factor binding protein 7 (IGFBP7), a negative regulator of IGF1 receptor (IGF1R) activity, induces apoptosis of AML cells and sensitizes AML cells to chemotherapy-induced cell death. Since it has been shown that IGF1R inhibitors can eliminate therapy-resistant cells by modifying their chromatin state, we hypothesized that IGFBP7 may also have the capacity to modify an epigenetic state and unlock the ATRA-driven differentiation response. To this end, we generated APL cell lines with down- or upregulated IGFBP7 levels and demonstrated that knockdown of IGFBP7 in NB4 cells blocked ATRA-induced differentiation, whereas overexpression of IGFBP7 led to an 8-fold increase in differentiation in the presence of low concentrations of ATRA, together suggesting a role for IGFBP7 in ATRA-induced differentiation in APL cells. Strategies to increase efficacy of ATRA-based therapy might also improve treatment outcomes for non-APL AML, and therefore we investigated the potential of IGFBP7 to induce susceptibility for ATRA-driven differentiation in this group. ATRA and IGFBP7 treatment of non-APL AML cell lines and primary AML cells derived from patients at diagnosis demonstrated an enhanced efficiency of the combination therapy to induce differentiation of myeloid CD45dimCD33+ AML cells (2.5-fold increase in CD11b-expression) and/or to reduce viability of AML CD45dim cells as compared to single treatments (from 30-39% to 70% reduction upon IGFBP7, ATRA or combination therapy, respectively), in 50% of tested primary AML samples, while this combination ther