IGFBP7 Induces Differentiation and Loss of Survival of Human Acute Myeloid Leukemia Stem Cells without Affecting Normal Hematopoiesis

Han J. M. P. Verhagen, Noortje van Gils, Tania Martiañez, Anna van Rhenen, Arjo Rutten, Fedor Denkers, David C. de Leeuw, Marjon A. Smit, Mei-Ling Tsui, Louise L. E. de Vos Klootwijk, Renee X. Menezes, Meyram Çil, Margaretha G. M. Roemer, Eline Vermue, Stan Heukelom, Sonja Zweegman, Jeroen J. W. M. Janssen, Gert J. Ossenkoppele, Gerrit Jan Schuurhuis, Linda Smit

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)3021-3035.e5
JournalCell Reports
Volume25
Issue number11
Early online date2018
DOIs
Publication statusPublished - 11 Dec 2018

Cite this

Verhagen, Han J. M. P. ; van Gils, Noortje ; Martiañez, Tania ; van Rhenen, Anna ; Rutten, Arjo ; Denkers, Fedor ; de Leeuw, David C. ; Smit, Marjon A. ; Tsui, Mei-Ling ; de Vos Klootwijk, Louise L. E. ; Menezes, Renee X. ; Çil, Meyram ; Roemer, Margaretha G. M. ; Vermue, Eline ; Heukelom, Stan ; Zweegman, Sonja ; Janssen, Jeroen J. W. M. ; Ossenkoppele, Gert J. ; Schuurhuis, Gerrit Jan ; Smit, Linda. / IGFBP7 Induces Differentiation and Loss of Survival of Human Acute Myeloid Leukemia Stem Cells without Affecting Normal Hematopoiesis. In: Cell Reports. 2018 ; Vol. 25, No. 11. pp. 3021-3035.e5.
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title = "IGFBP7 Induces Differentiation and Loss of Survival of Human Acute Myeloid Leukemia Stem Cells without Affecting Normal Hematopoiesis",
abstract = "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.",
author = "Verhagen, {Han J. M. P.} and {van Gils}, Noortje and Tania Martia{\~n}ez and {van Rhenen}, Anna and Arjo Rutten and Fedor Denkers and {de Leeuw}, {David C.} and Smit, {Marjon A.} and Mei-Ling Tsui and {de Vos Klootwijk}, {Louise L. E.} and Menezes, {Renee X.} and Meyram {\cC}il and Roemer, {Margaretha G. M.} and Eline Vermue and Stan Heukelom and Sonja Zweegman and Janssen, {Jeroen J. W. M.} and Ossenkoppele, {Gert J.} and Schuurhuis, {Gerrit Jan} and Linda Smit",
note = "Copyright {\circledC} 2018 The Authors. Published by Elsevier Inc. All rights reserved.",
year = "2018",
month = "12",
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doi = "10.1016/j.celrep.2018.11.062",
language = "English",
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IGFBP7 Induces Differentiation and Loss of Survival of Human Acute Myeloid Leukemia Stem Cells without Affecting Normal Hematopoiesis. / Verhagen, Han J. M. P.; van Gils, Noortje; Martiañez, Tania; van Rhenen, Anna; Rutten, Arjo; Denkers, Fedor; de Leeuw, David C.; Smit, Marjon A.; Tsui, Mei-Ling; de Vos Klootwijk, Louise L. E.; Menezes, Renee X.; Çil, Meyram; Roemer, Margaretha G. M.; Vermue, Eline; Heukelom, Stan; Zweegman, Sonja; Janssen, Jeroen J. W. M.; Ossenkoppele, Gert J.; Schuurhuis, Gerrit Jan; Smit, Linda.

In: Cell Reports, Vol. 25, No. 11, 11.12.2018, p. 3021-3035.e5.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - IGFBP7 Induces Differentiation and Loss of Survival of Human Acute Myeloid Leukemia Stem Cells without Affecting Normal Hematopoiesis

AU - Verhagen, Han J. M. P.

AU - van Gils, Noortje

AU - Martiañez, Tania

AU - van Rhenen, Anna

AU - Rutten, Arjo

AU - Denkers, Fedor

AU - de Leeuw, David C.

AU - Smit, Marjon A.

AU - Tsui, Mei-Ling

AU - de Vos Klootwijk, Louise L. E.

AU - Menezes, Renee X.

AU - Çil, Meyram

AU - Roemer, Margaretha G. M.

AU - Vermue, Eline

AU - Heukelom, Stan

AU - Zweegman, Sonja

AU - Janssen, Jeroen J. W. M.

AU - Ossenkoppele, Gert J.

AU - Schuurhuis, Gerrit Jan

AU - Smit, Linda

N1 - Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2018/12/11

Y1 - 2018/12/11

N2 - 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.

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.

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U2 - 10.1016/j.celrep.2018.11.062

DO - 10.1016/j.celrep.2018.11.062

M3 - Article

VL - 25

SP - 3021-3035.e5

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 11

ER -