PMID- 30540936 OWN - NLM STAT- MEDLINE DCOM- 20191203 LR - 20191203 IS - 2211-1247 (Electronic) VI - 25 IP - 11 DP - 2018 Dec 11 TI - IGFBP7 Induces Differentiation and Loss of Survival of Human Acute Myeloid Leukemia Stem Cells without Affecting Normal Hematopoiesis. PG - 3021-3035.e5 LID - S2211-1247(18)31838-2 [pii] LID - 10.1016/j.celrep.2018.11.062 [doi] AB - Leukemic stem cells (LSCs) are thought to be the major cause of the recurrence of acute myeloid leukemia (AML) due to their potential for self-renewal. To identify therapeutic strategies targeting LSCs, while sparing healthy hematopoietic stem cells (HSCs), we performed gene expression profiling of LSCs, HSCs, and leukemic progenitors all residing within the same AML bone marrow and identified insulin-like growth factor-binding protein 7 (IGFBP7) as differentially expressed. Low IGFBP7 is a feature of LSCs and is associated with reduced chemotherapy sensitivity. Enhancing IGFBP7 by overexpression or addition of recombinant human IGFBP7 (rhIGFBP7) resulted in differentiation, inhibition of cell survival, and increased chemotherapy sensitivity of primary AML cells. Adding rhIGFBP7 reduced leukemic stem and/or progenitor survival and reversed a stem-like gene signature, but it had no influence on normal hematopoietic stem cell survival. Our data suggest a potential clinical utility of the addition of rhIGFBP7 to current chemotherapy regimens to decrease AML relapse rates. CI - Copyright (c) 2018 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Verhagen, Han J M P AU - Verhagen HJMP AD - Department of Hematology, Cancer Center Amsterdam (CCA), Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands. FAU - van Gils, Noortje AU - van Gils N AD - Department of Hematology, Cancer Center Amsterdam (CCA), Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands. FAU - Martianez, Tania AU - Martianez T AD - Department of Hematology, Cancer Center Amsterdam (CCA), Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands. FAU - van Rhenen, Anna AU - van Rhenen A AD - Department of Hematology, Cancer Center Amsterdam (CCA), Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands. FAU - Rutten, Arjo AU - Rutten A AD - Department of Hematology, Cancer Center Amsterdam (CCA), Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands. FAU - Denkers, Fedor AU - Denkers F AD - Department of Hematology, Cancer Center Amsterdam (CCA), Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands. FAU - de Leeuw, David C AU - de Leeuw DC AD - Department of Hematology, Cancer Center Amsterdam (CCA), Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands. FAU - Smit, Marjon A AU - Smit MA AD - Department of Hematology, Cancer Center Amsterdam (CCA), Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands. FAU - Tsui, Mei-Ling AU - Tsui ML AD - Department of Hematology, Cancer Center Amsterdam (CCA), Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands. FAU - de Vos Klootwijk, Louise L E AU - de Vos Klootwijk LLE AD - Department of Hematology, Cancer Center Amsterdam (CCA), Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands. FAU - Menezes, Renee X AU - Menezes RX AD - Department of Epidemiology and Biostatistics, Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands. FAU - Cil, Meyram AU - Cil M AD - Department of Hematology, Cancer Center Amsterdam (CCA), Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands. FAU - Roemer, Margaretha G M AU - Roemer MGM AD - Department of Hematology, Cancer Center Amsterdam (CCA), Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands. FAU - Vermue, Eline AU - Vermue E AD - Department of Hematology, Cancer Center Amsterdam (CCA), Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands. FAU - Heukelom, Stan AU - Heukelom S AD - Department of Radiology & Nuclear Medicine, Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands. FAU - Zweegman, Sonja AU - Zweegman S AD - Department of Hematology, Cancer Center Amsterdam (CCA), Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands. FAU - Janssen, Jeroen J W M AU - Janssen JJWM AD - Department of Hematology, Cancer Center Amsterdam (CCA), Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands. FAU - Ossenkoppele, Gert J AU - Ossenkoppele GJ AD - Department of Hematology, Cancer Center Amsterdam (CCA), Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands. FAU - Schuurhuis, Gerrit Jan AU - Schuurhuis GJ AD - Department of Hematology, Cancer Center Amsterdam (CCA), Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands. FAU - Smit, Linda AU - Smit L AD - Department of Hematology, Cancer Center Amsterdam (CCA), Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands. Electronic address: li.smit@vumc.nl. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Cell Rep JT - Cell reports JID - 101573691 RN - 0 (Insulin-Like Growth Factor Binding Proteins) RN - 0 (Recombinant Proteins) RN - 0 (insulin-like growth factor binding protein-related protein 1) SB - IM MH - Bone Marrow/pathology MH - *Cell Differentiation/drug effects MH - Cell Survival/drug effects MH - Clone Cells MH - *Hematopoiesis/drug effects MH - Hematopoietic Stem Cells/drug effects/metabolism MH - Humans MH - Insulin-Like Growth Factor Binding Proteins/*metabolism MH - Leukemia, Myeloid, Acute/drug therapy/*pathology MH - Neoplastic Stem Cells/drug effects/metabolism/pathology MH - Recombinant Proteins/pharmacology OTO - NOTNLM OT - IGFBP7 OT - acute myeloid leukemia OT - chemotherapy sensitivity OT - hematopoietic stem cells OT - leukemic stem cells EDAT- 2018/12/13 06:00 MHDA- 2019/12/04 06:00 CRDT- 2018/12/13 06:00 PHST- 2018/03/08 00:00 [received] PHST- 2018/10/09 00:00 [revised] PHST- 2018/11/14 00:00 [accepted] PHST- 2018/12/13 06:00 [entrez] PHST- 2018/12/13 06:00 [pubmed] PHST- 2019/12/04 06:00 [medline] AID - S2211-1247(18)31838-2 [pii] AID - 10.1016/j.celrep.2018.11.062 [doi] PST - ppublish SO - Cell Rep. 2018 Dec 11;25(11):3021-3035.e5. doi: 10.1016/j.celrep.2018.11.062.