SL-401 and SL-501, targeted therapeutics directed at the interleukin-3 receptor, inhibit the growth of leukaemic cells and stem cells in advanced phase chronic myeloid leukaemia

Olga Frolova, Juliana Benito, Chris Brooks, Rui Yu Wang, Borys Korchin, Eric K. Rowinsky, Jorge Cortes, Hagop Kantarjian, Michael Andreeff, Arthur E. Frankel, Marina Konopleva

Research output: Contribution to journalArticle

Abstract

While imatinib and other tyrosine kinase inhibitors (TKIs) are highly efficacious in the treatment of chronic myeloid leukaemia (CML), some patients become refractory to these therapies. After confirming that interleukin-3 receptor (IL3R, CD123) is highly expressed on CD34+/CD38- BCR-ABL1+ CML stem cells, we investigated whether targeting IL3R with diphtheria toxin (DT)-IL3 fusion proteins SL-401 (DT388-IL3) and SL-501 (DT388-IL3[K116W]) could eradicate these stem cells. SL-401 and SL-501 inhibited cell growth and induced apoptosis in the KBM5 cell line and its TKI-resistant KBM5-STI subline. Combinations of imatinib with these agents increased apoptosis in KBM5 and in primary CML cells. In six primary CML samples, including CML cells harbouring the ABL1 T315I mutation, SL-401 and SL-501 decreased the absolute numbers of viable CD34+/CD38-/CD123+ CML progenitor cells by inducing apoptosis. IL3-targeting agents reduced clonogenic growth and diminished the fraction of primitive long-term culture-initiating cells in samples from patients with advanced phase CML that were resistant to TKIs or harboured an ABL1 mutation. Survival was also extended in a mouse model of primary TKI-resistant CML blast crisis. These data suggest that the DT-IL3 fusion proteins, SL-401 and SL-501, deplete CML stem cells and may increase the effectiveness of current CML treatment, which principally targets tumour bulk.

Original languageEnglish (US)
Pages (from-to)862-874
Number of pages13
JournalBritish Journal of Haematology
Volume166
Issue number6
DOIs
StatePublished - Sep 2014
Externally publishedYes

Fingerprint

Interleukin-3 Receptors
Leukemia, Myeloid, Chronic Phase
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Stem Cells
Growth
Myeloid Progenitor Cells
Protein-Tyrosine Kinases
Diphtheria Toxin
Therapeutics
Myeloid Cells
Apoptosis
Blast Crisis
Mutation
Sexually Transmitted Diseases
Cell Culture Techniques

Keywords

  • Chronic myeloid leukaemia
  • Interleukin-3 receptor
  • Leukaemic stem cells
  • SL-401
  • SL-501

ASJC Scopus subject areas

  • Hematology

Cite this

SL-401 and SL-501, targeted therapeutics directed at the interleukin-3 receptor, inhibit the growth of leukaemic cells and stem cells in advanced phase chronic myeloid leukaemia. / Frolova, Olga; Benito, Juliana; Brooks, Chris; Wang, Rui Yu; Korchin, Borys; Rowinsky, Eric K.; Cortes, Jorge; Kantarjian, Hagop; Andreeff, Michael; Frankel, Arthur E.; Konopleva, Marina.

In: British Journal of Haematology, Vol. 166, No. 6, 09.2014, p. 862-874.

Research output: Contribution to journalArticle

Frolova, Olga ; Benito, Juliana ; Brooks, Chris ; Wang, Rui Yu ; Korchin, Borys ; Rowinsky, Eric K. ; Cortes, Jorge ; Kantarjian, Hagop ; Andreeff, Michael ; Frankel, Arthur E. ; Konopleva, Marina. / SL-401 and SL-501, targeted therapeutics directed at the interleukin-3 receptor, inhibit the growth of leukaemic cells and stem cells in advanced phase chronic myeloid leukaemia. In: British Journal of Haematology. 2014 ; Vol. 166, No. 6. pp. 862-874.
@article{df964641731a4a6e9f7a86e616e05fcc,
title = "SL-401 and SL-501, targeted therapeutics directed at the interleukin-3 receptor, inhibit the growth of leukaemic cells and stem cells in advanced phase chronic myeloid leukaemia",
abstract = "While imatinib and other tyrosine kinase inhibitors (TKIs) are highly efficacious in the treatment of chronic myeloid leukaemia (CML), some patients become refractory to these therapies. After confirming that interleukin-3 receptor (IL3R, CD123) is highly expressed on CD34+/CD38- BCR-ABL1+ CML stem cells, we investigated whether targeting IL3R with diphtheria toxin (DT)-IL3 fusion proteins SL-401 (DT388-IL3) and SL-501 (DT388-IL3[K116W]) could eradicate these stem cells. SL-401 and SL-501 inhibited cell growth and induced apoptosis in the KBM5 cell line and its TKI-resistant KBM5-STI subline. Combinations of imatinib with these agents increased apoptosis in KBM5 and in primary CML cells. In six primary CML samples, including CML cells harbouring the ABL1 T315I mutation, SL-401 and SL-501 decreased the absolute numbers of viable CD34+/CD38-/CD123+ CML progenitor cells by inducing apoptosis. IL3-targeting agents reduced clonogenic growth and diminished the fraction of primitive long-term culture-initiating cells in samples from patients with advanced phase CML that were resistant to TKIs or harboured an ABL1 mutation. Survival was also extended in a mouse model of primary TKI-resistant CML blast crisis. These data suggest that the DT-IL3 fusion proteins, SL-401 and SL-501, deplete CML stem cells and may increase the effectiveness of current CML treatment, which principally targets tumour bulk.",
keywords = "Chronic myeloid leukaemia, Interleukin-3 receptor, Leukaemic stem cells, SL-401, SL-501",
author = "Olga Frolova and Juliana Benito and Chris Brooks and Wang, {Rui Yu} and Borys Korchin and Rowinsky, {Eric K.} and Jorge Cortes and Hagop Kantarjian and Michael Andreeff and Frankel, {Arthur E.} and Marina Konopleva",
year = "2014",
month = "9",
doi = "10.1111/bjh.12978",
language = "English (US)",
volume = "166",
pages = "862--874",
journal = "British Journal of Haematology",
issn = "0007-1048",
publisher = "Wiley-Blackwell",
number = "6",

}

TY - JOUR

T1 - SL-401 and SL-501, targeted therapeutics directed at the interleukin-3 receptor, inhibit the growth of leukaemic cells and stem cells in advanced phase chronic myeloid leukaemia

AU - Frolova, Olga

AU - Benito, Juliana

AU - Brooks, Chris

AU - Wang, Rui Yu

AU - Korchin, Borys

AU - Rowinsky, Eric K.

AU - Cortes, Jorge

AU - Kantarjian, Hagop

AU - Andreeff, Michael

AU - Frankel, Arthur E.

AU - Konopleva, Marina

PY - 2014/9

Y1 - 2014/9

N2 - While imatinib and other tyrosine kinase inhibitors (TKIs) are highly efficacious in the treatment of chronic myeloid leukaemia (CML), some patients become refractory to these therapies. After confirming that interleukin-3 receptor (IL3R, CD123) is highly expressed on CD34+/CD38- BCR-ABL1+ CML stem cells, we investigated whether targeting IL3R with diphtheria toxin (DT)-IL3 fusion proteins SL-401 (DT388-IL3) and SL-501 (DT388-IL3[K116W]) could eradicate these stem cells. SL-401 and SL-501 inhibited cell growth and induced apoptosis in the KBM5 cell line and its TKI-resistant KBM5-STI subline. Combinations of imatinib with these agents increased apoptosis in KBM5 and in primary CML cells. In six primary CML samples, including CML cells harbouring the ABL1 T315I mutation, SL-401 and SL-501 decreased the absolute numbers of viable CD34+/CD38-/CD123+ CML progenitor cells by inducing apoptosis. IL3-targeting agents reduced clonogenic growth and diminished the fraction of primitive long-term culture-initiating cells in samples from patients with advanced phase CML that were resistant to TKIs or harboured an ABL1 mutation. Survival was also extended in a mouse model of primary TKI-resistant CML blast crisis. These data suggest that the DT-IL3 fusion proteins, SL-401 and SL-501, deplete CML stem cells and may increase the effectiveness of current CML treatment, which principally targets tumour bulk.

AB - While imatinib and other tyrosine kinase inhibitors (TKIs) are highly efficacious in the treatment of chronic myeloid leukaemia (CML), some patients become refractory to these therapies. After confirming that interleukin-3 receptor (IL3R, CD123) is highly expressed on CD34+/CD38- BCR-ABL1+ CML stem cells, we investigated whether targeting IL3R with diphtheria toxin (DT)-IL3 fusion proteins SL-401 (DT388-IL3) and SL-501 (DT388-IL3[K116W]) could eradicate these stem cells. SL-401 and SL-501 inhibited cell growth and induced apoptosis in the KBM5 cell line and its TKI-resistant KBM5-STI subline. Combinations of imatinib with these agents increased apoptosis in KBM5 and in primary CML cells. In six primary CML samples, including CML cells harbouring the ABL1 T315I mutation, SL-401 and SL-501 decreased the absolute numbers of viable CD34+/CD38-/CD123+ CML progenitor cells by inducing apoptosis. IL3-targeting agents reduced clonogenic growth and diminished the fraction of primitive long-term culture-initiating cells in samples from patients with advanced phase CML that were resistant to TKIs or harboured an ABL1 mutation. Survival was also extended in a mouse model of primary TKI-resistant CML blast crisis. These data suggest that the DT-IL3 fusion proteins, SL-401 and SL-501, deplete CML stem cells and may increase the effectiveness of current CML treatment, which principally targets tumour bulk.

KW - Chronic myeloid leukaemia

KW - Interleukin-3 receptor

KW - Leukaemic stem cells

KW - SL-401

KW - SL-501

UR - http://www.scopus.com/inward/record.url?scp=84907597109&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907597109&partnerID=8YFLogxK

U2 - 10.1111/bjh.12978

DO - 10.1111/bjh.12978

M3 - Article

C2 - 24942980

AN - SCOPUS:84907597109

VL - 166

SP - 862

EP - 874

JO - British Journal of Haematology

JF - British Journal of Haematology

SN - 0007-1048

IS - 6

ER -