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Notch in Leukemia

  • Anna C. McCarter
  • Qing Wang
  • Mark Chiang
Chapter
Part of the Advances in Experimental Medicine and Biology book series (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.

Keywords

Notch T-cell acute lymphoblastic leukemia Chronic lymphocytic leukemia MYC AKT 

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 P3

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

Notes

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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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Cell and Molecular Biology ProgramUniversity of MichiganAnn ArborUSA
  2. 2.Division of Hematology-Oncology, Department of Internal MedicineUniversity of MichiganAnn ArborUSA

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