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Notch in Leukemia

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Molecular Mechanisms of Notch Signaling

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1066))

Abstract

Notch is commonly activated in lymphoid malignancies through ligand-independent and ligand-dependent mechanisms. In T-cell acute lymphoblastic leukemia/lymphoma (T-ALL), ligand-independent activation predominates. Negative Regulatory Region (NRR) mutations trigger supraphysiological Notch1 activation by exposing the S2 site to proteolytic cleavage in the absence of ligand. Subsequently, cleavage at the S3 site generates the activated form of Notch, intracellular Notch (ICN). In contrast to T-ALL, in mature lymphoid neoplasms such as chronic lymphocytic leukemia (CLL), the S2 cleavage site is exposed through ligand-receptor interactions. Thus, agents that disrupt ligand-receptor interactions might be useful for treating these malignancies. Notch activation can be enhanced by mutations that delete the C-terminal proline (P), glutamic acid (E), serine (S), and threonine (T) (PEST) domain. These mutations do not activate the Notch pathway per se, but rather impair degradation of ICN. In this chapter, we review the mechanisms of Notch activation and the importance of Notch for the genesis and maintenance of lymphoid malignancies. Unfortunately, targeting the Notch pathway with pan-Notch inhibitors in clinical trials has proven challenging. These clinical trials have encountered dose-limiting on-target toxicities and primary resistance. Strategies to overcome these challenges have emerged from the identification and improved understanding of direct oncogenic Notch target genes. Other strategies have arisen from new insights into the “nuclear context” that selectively directs Notch functions in lymphoid cancers. This nuclear context is created by factors that co-bind ICN at cell-type specific transcriptional regulatory elements. Disrupting the functions of these proteins or inhibiting downstream oncogenic pathways might combat cancer without the intolerable side effects of pan-Notch inhibition.

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Abbreviations

ADAM10:

A Disintegrin And Metalloproteinase Domain-Containing Protein 10

AF4p12:

ALL1-Fused Gene From Chromosome 4p12 Protein

AITL:

Angioimmunoblastic T-Cell Lymphomas

AKT:

AK Mouse Transforming

AMKL:

Acute Megakaryocytic Leukemia

AML:

Acute Myeloid Leukemia

AML1:

Acute Myeloid Leukemia 1

APL:

Acute Promyelocytic Leukemia

APH1A:

Anterior Pharynx Defective 1 Homolog A

BBC3:

BCL-2 Binding Component 3

BCL2:

B-Cell CLL/Lymphoma 2

BCL6:

B-Cell CLL/Lymphoma 6

BCL11B:

B-Cell CLL/Lymphoma 11B

BCR:

B-Cell Receptor

BHLH:

Basic Helix-Loop-Helix

BLK:

B Lymphocyte Kinase

BLNK:

B-cell Linker Protein

BM:

Bone Marrow

BPTES:

Bis-2-(5-Phenylacetamido-1,2,4-Thiadiazol-2-Yl)Ethyl Sulfide

BRD4:

Bromodomain Containing 4

CARM1:

Coactivator-associated Arginine Methyltransferase 1

CAS9:

CRISPR Associated Protein 9

CBFβ:

Core Binding Factor β

CCNC:

Cyclin C

CCND1:

Cyclin D1

CCND3:

Cyclin D3

CCNE1:

Cyclin E1

CCR7

C-C Chemokine Receptor Type 7

CDK3:

Cyclin-dependent kinase 3

CDK4:

Cyclin-dependent kinase 4

CDK6:

Cyclin-dependent kinase 6

CDK8:

Cyclin-dependent kinase 8

CDK19:

Cyclin-dependent kinase 19

CDKN1B:

Cyclin Dependent Kinase Inhibitor 1B

CDKN2:

Cyclin Dependent Kinase Inhibitor 2D

CHD4:

Chromodomain Helicase DNA Binding Protein 4

ChIP:

Chromatin Immuno-precipitation

CLL:

Chronic Lymphocytic Leukemia

CR2:

Complement C3d Receptor 2

CRISPR:

Clustered Regularly Interspaced Short Palindromic Repeats

CXCR4:

C-X-C Chemokine Receptor Type 4

CYLD:

Ubiquitin Carboxyl-Terminal Hydrolase

DDX5:

DEAD-box RNA Helicase 5

DEPTOR:

DEP Domain Containing MTOR Interacting Protein

DLL1:

Delta-Like 1

DLL4:

Delta-Like 4

DLX5:

Distal-Less Homeobox 5

DN-MAML:

Dominant-Negative Mastermind

DNA:

Deoxyribonucleic Acid

DTX1:

Deltex E3 Ubiquitin Ligase 1

E2A:

E2A Immunoglobulin Enhancer-Binding Factor E12/E47

EBNA2:

Epstein–Barr Nuclear Antigen 2

EBV:

Epstein–Barr Virus

EIF2A:

Eukaryotic Translation Initiation Factor 2A

ERK:

Extracellular Signal-regulated Kinase

ETO:

Eight-Twenty One

ETS1:

E26 Avian Leukemia Oncogene 1

ETP-ALL:

Early T-cell Precursor Acute Lymphoblastic Leukemia

FBXW7:

F-Box and WD Repeat-Containing Protein 7

FDA:

Food and Drug Administration

FL:

Follicular Lymphoma

G-CSF:

Granulocyte-Colony Stimulating Factor

GABPA:

GA Binding Protein Transcription Factor Alpha Subunit

GATA3:

GATA Binding Protein 3

GATAD2B:

GATA Zinc Finger Domain Containing 2B

GEMM:

Genetically Engineered Mouse Model Of T-ALL

GI:

Gastrointestinal

GOF:

Gain-Of-Function

GSI:

γ-Secretase Inhibitor

HD:

Heterodimerization Domain

HDAC1:

Histone Deacetylase 1

HEB:

E2A/Hela E Box-Binding

HES1:

Hairy And Enhancer Of Split 1

HSC:

Hematopoietic Stem Cell

HSP90:

Heat Shock Protein 90

ICN1:

Intracellular Notch1

ID3:

Inhibitor Of DNA Binding 3 HLH Protein

IGF1R:

Insulin Like Growth Factor 1 Receptor

IHC:

Immunohistochemistry

IKK:

Inhibitor Of Kappa-B Kinase

IKKα:

Inhibitor Of Kappa-B Kinase Subunit Alpha

IKKβ:

Inhibitor Of Kappa-B Kinase Subunit Beta

IKZF1:

Ikaros Family Zinc Finger 1

IL7R:

Interleukin 7 Receptor

INK4:

Inhibitor of Cyclin-Dependent Kinase 4

IRF4:

Interferon Regulatory Factor 4

KRAS:

Kirsten Rat Sarcoma Viral Oncogene Homolog

JME:

Juxtamembrane Extracellular

JUN:

Ju-nana (Japanese number 17)

LEF1:

Lymphoid Enhancer Binding Factor 1

LIC:

Leukemia-Initiating Cells

LMO2:

Lim Domain Only 2

LN:

Lymph Node

LNR:

Lin12/Notch Repeats

LUNAR1:

Leukemia-Associated Non-Coding IGF1R Activator RNA 1

LSC:

Leukemia Stem Cells

LSD1:

Lysine (K)-Specific Demethylase 1A

LYN:

Lck/Yes-Related Novel Protein Tyrosine Kinase

MAL:

Megakaryocytic Acute Leukemia

MAML:

Mastermind-Like

MCL:

Mantle Cell Lymphoma

MCL1:

Myeloid Leukemia Cell Differentiation Protein 1

MTOR:

Mechanistic Target Of Rapamycin

MYC:

Myelocytomatosis proto-oncogene

N-ME:

Notch-MYC enhancer

NDME:

Notch-dependent MYC enhancer

NEMO:

NF-κB Essential Modulator

NF-κB:

Nuclear Factor-κB

NFκB2:

Nuclear Factor Of Kappa Light Polypeptide Gene Enhancer In B Cells 2

NOS:

Not Otherwise Specified

NRR:

Negative Regulatory Region

NURD:

Nucleosome Remodeling Deacetylase

OTT:

One-Twenty Two

p70S6K:

Ribosomal protein S6 kinase beta-1

PB1:

Polybromo 1

PBAF:

Polybromo-Associated BRG1- Or HBRM-Associated Factors

PCAF:

P300/CBP-Associated Factor

PCR:

Polymerase Chain Reaction

PDX:

Patient-Derived Xenograft

PEST

Proline (P), Glutamic Acid (E), Serine (S), And Threonine (T)

PHF8:

PHD Finger Protein 8

PI3K:

Phosphatidylinositol 4,5-Bisphosphate 3-Kinase

PIAS:

Protein Inhibitor of Activated STAT

PIK3CD:

Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Delta

PIP3:

Phosphatidylinositol (3,4,5)-trisphosphate P 3

PLCγ:

Phospholipase Cγ

PML:

Promyelocytic Leukemia Locus Gene

POFUT1:

Protein O-Fucosyltransferase 1

PRL2:

Phosphatase of Regenerating Liver

PTCRA invariant:

preTα chain of the pre-T cell receptor

PTEN:

Phosphatase And Tensin Homolog

QRT-PCR:

Quantitative Real Time PCR

RARA:

Retinoic Acid Receptor-Alpha

RAS:

Rat Sarcoma virus oncogene

RB:

Retinoblastoma Protein

RBBP4:

RB Binding Protein 4, Chromatin Remodeling Factor

RBPJ:

Recombination Signal Binding Protein For Immunoglobulin Kappa J Region

RELB:

Relaxed B Proto-Oncogene

RNA:

Ribonucleic Acid

RNAPII:

RNA Polymerase II

RNF40:

Ring Finger Protein 40

RUNX1:

Runt Related Transcription Factor 1

SAHM:

MAM-like Stapled Peptides

SERCA:

Sarco/Endoplasmic Reticulum Calcium ATPase

SLL:

Small Lymphocytic Lymphoma

SKP2:

S-Phase Kinase Associated Protein 2

STUB1:

STIP1 Homology And U-Box Containing Protein 1

SYK:

Spleen Tyrosine Kinase

T-ALL:

T-cell Acute Lymphoblastic Leukemia

TAL1:

T-cell Acute Lymphoblastic Leukemia 1

TCF1:

Transcription Factor 1

TCRB:

T-cell Receptor β

TP53:

Tumor Protein P53

TPR:

Tetratricopeptide Repeat

TRIB2:

Tribbles Pseudokinase 2

TSS:

Transcriptional Start Site

UTR:

Untranslated Region

ZFP36L1:

Zinc Finger Protein C3H Type 36-Like 1

ZFP36L2:

Zinc Finger Protein C3H Type 36-Like 2

ZMIZ1:

Zinc Finger MIZ-Type Containing 1

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Acknowledgements

We thank members of the Maillard and Chiang laboratories for helpful discussions and review of the manuscript. A.M. was supported by the NIH Ruth L. Kirschstein National Research Service Award (F30CA228228), the NIH Cellular and Molecular Biology Training Grant (T32-GM007315), the MSTP Training Grant (T32-GM007863-37), and the Rackham Graduate Student Research Grant. Q.W. and M.C. were supported by the NIH (R01CA196604). M.C. was also supported by the Rally Foundation for Childhood Cancer Research and the Alex’s Lemonade Stand Foundation. The authors apologize to those whose work could not be mentioned owing to space limitations.

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  1. Cell and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA

    Anna C. McCarter

  2. Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Qing Wang & Mark Chiang

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  1. Institute of Biochemistry, University of Giessen, Giessen, Germany

    Tilman Borggrefe

  2. Institute of Biochemistry, University of Giessen, Giessen, Germany

    Benedetto Daniele Giaimo

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McCarter, A.C., Wang, Q., Chiang, M. (2018). Notch in Leukemia. In: Borggrefe, T., Giaimo, B. (eds) Molecular Mechanisms of Notch Signaling. Advances in Experimental Medicine and Biology, vol 1066. Springer, Cham. https://doi.org/10.1007/978-3-319-89512-3_18

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