Abstract 2339: IGFBP7 eradicates leukemic stem and progenitor cells in acute myeloid leukemia
Authors: Verhagen Han , Smit Marjon , de Leeuw David , Rutten Arjo , Tsui Mei-Ling , Denkers Fedor , Terwijn Monique , Celie Patrick , Ossenkoppele Gert , Schuurhuis Gerrit Jan , Smit Linda 
Published: August 2015

Despite high complete remission rates after chemotherapy treatment, only 30-40% of acute myeloid leukemia (AML) patients (&lt; 60 years) survive five years after diagnosis. This poor prognosis is mainly due to relapse which is thought to be initiated by a subpopulation of leukemic cells with stem cell-like features that survived the treatment, often referred to as leukemic stem cells (LSC). The development of novel alternative therapies, specifically targeting these LSC, are needed to prevent relapse and improve AML outcome. To develop these anti-LSC therapies, identification of genes differentially expressed between LSC and the AML bulk and the normal HSC, still residing within the AML bone marrow, is critical. Studying these differences is most relevant in cell fractions obtained from the same AML bone marrow, taking into account the effects of the leukemic microenvironment on these cell compartments.

Since LSC and HSC share the same immunophenotype (CD34+CD38-), we and others identified markers including CLL-1 as well as scatter properties, to distinguish leukemic from normal stem cells. By these properties we purified LSC, HSC and progenitors fractions from AML bone marrow. Gene expression profiling revealed the insulin-like growth factor binding-protein-7 (IGFBP7) as differentially expressed between LSC and HSC and between LSC and the AML bulk. IGFBP7 is a secreted tumor suppressor and based on our expression data we hypothesized that IGFBP7 might induce the eradication of LSC.

Using a knockdown strategy, we show that decreased levels of IGFBP7 in AML cell lines result in decreased sensitivity to chemotherapy. Moreover, we show that both IGFBP7 overexpression and recombinant human IGFBP7 (rhIGFBP7) reduces the survival of leukemic stem and progenitor cells from AML patients. Incubation with rhIGFBP7 showed decreased survival of leukemic blasts while sparing healthy cells. Most importantly, IGFBP7 significantly reduces human leukemic engraftment of primary AML cells in immune-deficient NOD/SCID-IL2γ knockout (NSG) mice.

Altogether, LSC have reduced levels of IGFBP7 which might be responsible for their decreased sensitivity to chemotherapy. The eradication of LSC and leukemic progenitors can be accomplished by enhancing IGFBP7 levels, suggesting that AML patients might benefit from a combination of rhIGFBP7 and chemotherapy. This combination therapy might prevent relapse and improve AML outcome.

Citation Format: Han Verhagen, Marjon Smit, David de Leeuw, Arjo Rutten, Mei-Ling Tsui, Fedor Denkers, Monique Terwijn, Patrick Celie, Gert Ossenkoppele, Gerrit Jan Schuurhuis, Linda Smit. IGFBP7 eradicates leukemic stem and progenitor cells in acute myeloid leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2339. doi:10.1158/1538-7445.AM2015-2339