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Novel strategies for targeting leukemia stem cells: sounding the death knell for blood cancer

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Abstract

Background

Cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), are characterized by high self-renewal and multi-lineage differentiation capacities. CSCs are thought to play indispensable roles in the initiation, progression and metastasis of many types of cancer. Leukemias are thought to be initiated and maintained by a specific sub-type of CSC, the leukemia stem cell (LSC). An important feature of LSCs is their resistance to standard therapy, which may lead to relapse. Increasing efforts are aimed at developing novel therapeutic strategies that selectively target LSCs, while sparing their normal counterparts and, thus, minimizing adverse treatment-associated side-effects. These LSC targeting therapies aim to eradicate LSCs through affecting mechanisms that control their survival, self-renewal, differentiation, proliferation and cell cycle progression. Some LSC targeting therapies have already been proven successful in pre-clinical studies and they are now being tested in clinical studies, mainly in combination with conventional treatment regimens.

Conclusions

A growing body of evidence indicates that the selective targeting of LSCs represents a promising approach to improve disease outcome. Beyond doubt, the CSC hypothesis has added a new dimension to the area of anticancer research, thereby paving the way for shaping a new trend in cancer therapy.

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Abbreviations

HSCs:

Hematopoietic stem cells

HPCs:

Hematopoietic progenitor cells

LSCs:

Leukemic stem cells

AML:

Acute myeloid leukemia

CML:

Chronic myeloid leukemia

ALL:

Acute lymphoblastic leukemia

CML:

Chronic myeloid leukemia

CFCs:

Colony-forming cells

CDC:

Complement-dependent cytotoxicity

ADCC:

Antibody-dependent cellular cytotoxicity

ATP:

Adenosine triphosphate

FLT3:

Fms-like tyrosine kinase 3

ATRA:

All-trans retinoic acid

LXR:

Liver X receptor

DFO:

Deferoxamine

DFX:

Deferasirox

EP:

Eltrombopag

TPO-R:

Thrombopoietin receptor

RNS:

Reactive nitrogen species

BCL-2:

B-cell lymphoma 2

HDAC:

Histone deacetylase

DNMT:

DNA methyltransferase

PRC2:

Polycomb repressive complex 2

NF-kB:

Nuclear factor kappa B

PTL:

Parthenolide

PI3K:

Phosphatidylinositol 3 kinase

DNA-PK:

DNA-dependent protein kinase

MRP1:

Multidrug resistance-associated protein 1

FOXOs:

Forkhead transcription factors

HSPs:

Heat shock proteins

GMPs:

Granulocyte macrophage progenitors

Hh:

Hedgehog

PTCH:

Patched

TICs:

Tumor-initiating cells

TKIs:

Tyrosine kinase inhibitors

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Acknowledgments

We would like to thank all our colleagues for the insights that we have attempted to summarize. We apologize to the colleagues whose work could not be cited, owing to space limitations. SB is funded by the Iranian Council for Stem Cell Research and Technology Development (11/77230) and Tarbiat Modares University, Tehran, Iran. MLG is funded by the Irma T. Hirschl/Monique Weill-Caulier Trust, the US National Institutes of Health (NIH) (R01 CA172546; 5R01CA102031), and the Leukemia and Lymphoma Foundation. ACG is funded by the Instituto de Bebidas para la Salud y el Bienestar, México and the Fundación IMSS, México.

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  1. Oncology Research Unit, National Medical Center, IMSS, Oncology Hospital, Mexico City, Mexico

    Antonieta Chavez-Gonzalez

  2. Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, P.O. Box: 14115-154, Tehran, Iran

    Babak Bakhshinejad, Katayoon Pakravan & Sadegh Babashah

  3. Department of Medicine, Weill Medical College of Cornell University, 1300 York Ave, Box 113, New York, NY, 10065, USA

    Monica L. Guzman

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  1. Antonieta Chavez-Gonzalez
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Correspondence to Monica L. Guzman or Sadegh Babashah.

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Chavez-Gonzalez, A., Bakhshinejad, B., Pakravan, K. et al. Novel strategies for targeting leukemia stem cells: sounding the death knell for blood cancer. Cell Oncol. 40, 1–20 (2017). https://doi.org/10.1007/s13402-016-0297-1

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