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Signaling Pathways in Leukemic Stem Cells

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Leukemia Stem Cells in Hematologic Malignancies

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1143))

Abstract

Hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs) utilize many of the same signaling pathways for their maintenance and survival. In this review, we will focus on several signaling pathways whose roles have been extensively studied in both HSCs and LSCs. Our main focus will be on the PI3K/AKT/mTOR pathway and several of its regulators and downstream effectors. We will also discuss several other signaling pathways of particular importance in LSCs, including the WNT/β-catenin pathway, the NOTCH pathway, and the TGFβ pathway. For each of these pathways, we will emphasize differences in how these pathways operate in LSCs, compared to their function in HSCs, to highlight opportunities for the specific therapeutic targeting of LSCs. We will also highlight areas of crosstalk between multiple signaling pathways that may affect LSC function.

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Abbreviations

AML:

Acute myeloid leukemia

APC:

Adenomatous polyposis coli

BCR-ABL:

Fusion of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (ABL)

Cbf-1:

Centromere-binding protein 1

CLL:

Chronic lymphoblastic leukemia

CML:

Chronic myeloid leukemia

Co-Smad:

Common-partner Smad

DEPTOR:

DEP domain-containing mTOR-interacting protein

GPCRs:

G-protein-coupled receptors

GSK-3β:

Glycogen synthase kinase-3β

Hes-1:

Hairy and enhancer of split-1

HSC:

Hematopoietic stem cell

HSPC:

Hematopoietic stem and progenitor cell

IKK:

IκB kinase

I-Smad:

Inhibitory Smad

JNK:

Jun N-terminal kinase

LEF:

Lymphoid enhancer factor

Lrp5/6:

Lipoprotein receptor-related protein 5 or 6

LSC:

Leukemic stem cell

LSK:

Lineage negative, Sca1+, cKit-

MAPK:

Mitogen-activated protein kinase

MEK:

Mitogen-activated protein kinase

MLL:

Mixed lineage leukemia

mLST8:

Mammalian lethal with sec-13 protein 8

mSin1:

Mammalian stress-activated map kinase-interacting protein 1

mTOR:

Mechanistic target of rapamycin

mTORC1:

mTOR complex 1

mTORC2:

mTOR complex 2

NICD:

Notch intracellular domain

PDK1:

Pyruvate dehydrogenase kinase 1

PH:

Pleckstrin homology

PI3K:

Phosphatidylinositol 3-kinase

PIP2:

Phosphatidylinositol (3,4)-diphosphate

PIP3:

Phosphatidylinositol (3,4,5)-triphosphate

PORCN:

Porcupine

PRAS40:

Proline-rich Akt substrate 40 kDa

Protor1/2:

Protein observed with Rictor 1 and 2

PTEN:

Phosphatase and tensin homolog

Raptor:

Regulatory-associated protein of mammalian target of rapamycin

R-Smad:

Receptor-mediated Smad

RTK:

Receptor tyrosine kinase

SH2:

Src-homology 2

SHIP:

SH2-containing inositol 5′-phosphatase

SIRT1:

NAD-dependent deacetylase sirtuin-1

T-ALL:

T-cell acute lymphoblastic leukemia

TCF:

T-cell factor

TGFβ:

Transforming growth factor-beta

TKI:

Tyrosine kinase inhibitor

TSC1:

Tuberous sclerosis 1

TSC2:

Tuberous sclerosis 2

TβRI:

TGFβ-type I receptor

TβRII:

TGFβ-type II receptor

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Acknowledgments

We thank all members of the Gritsman lab for helpful discussions. We apologize to any authors whose work was not cited due to space limitations. This work was supported by the NIH/NCI R01 #R01CA196973 (KG), the American Society of Hematology (KG), the V Foundation for Cancer Research (KG), the Sinsheimer Foundation (KG), the Training Program in Cellular and Molecular Biology and Genetics at Albert Einstein College of Medicine #5T32GM007491-44 (LG), and the IRACDA-BETTR Postdoctoral Training Grant at Albert Einstein College of Medicine #2K12GM102779 (KA).

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The authors declare that no conflict of interest exists.

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Authors and Affiliations

  1. Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA

    Lindsay M. Gurska, Kristina Ames & Kira Gritsman

  2. Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA

    Lindsay M. Gurska, Kristina Ames & Kira Gritsman

  3. Department of Medical Oncology, Montefiore Hospital, Bronx, New York, USA

    Kira Gritsman

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  1. Lindsay M. Gurska
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  2. Kristina Ames
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Correspondence to Kira Gritsman .

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  1. Medical Research Institute, Wuhan University, Wuhan, Hubei, China

    Haojian Zhang

  2. Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    Shaoguang Li

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Gurska, L.M., Ames, K., Gritsman, K. (2019). Signaling Pathways in Leukemic Stem Cells. In: Zhang, H., Li, S. (eds) Leukemia Stem Cells in Hematologic Malignancies. Advances in Experimental Medicine and Biology, vol 1143. Springer, Singapore. https://doi.org/10.1007/978-981-13-7342-8_1

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