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
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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85057621446&origin=inward
U2 - https://doi.org/10.1016/j.celrep.2018.11.062
DO - https://doi.org/10.1016/j.celrep.2018.11.062
M3 - Article
C2 - 30540936
SN - 2211-1247
VL - 25
SP - 3021-3035.e5
JO - Cell reports
JF - Cell reports
IS - 11
ER -