PMID- 30030836
OWN - NLM
STAT- MEDLINE
DCOM- 20190219
LR  - 20190508
IS  - 0065-2598 (Print)
IS  - 0065-2598 (Linking)
VI  - 1066
DP  - 2018
TI  - Notch in Leukemia.
PG  - 355-394
LID - 10.1007/978-3-319-89512-3_18 [doi]
AB  - 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.
FAU - McCarter, Anna C
AU  - McCarter AC
AD  - Cell and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA.
FAU - Wang, Qing
AU  - Wang Q
AD  - Division of Hematology-Oncology, Department of Internal Medicine, University of 
      Michigan, Ann Arbor, MI, USA.
FAU - Chiang, Mark
AU  - Chiang M
AD  - Division of Hematology-Oncology, Department of Internal Medicine, University of 
      Michigan, Ann Arbor, MI, USA. markchia@umich.edu.
LA  - eng
GR  - T32 GM007315/GM/NIGMS NIH HHS/United States
GR  - T32 GM007863-37/GM/NIGMS NIH HHS/United States
GR  - R01 CA196604/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - United States
TA  - Adv Exp Med Biol
JT  - Advances in experimental medicine and biology
JID - 0121103
RN  - 0 (NOTCH1 protein, human)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Receptor, Notch1)
SB  - IM
MH  - Animals
MH  - Clinical Trials as Topic
MH  - Humans
MH  - Leukemia, Lymphocytic, Chronic, B-Cell/genetics/*metabolism/pathology
MH  - Neoplasm Proteins/genetics/*metabolism
MH  - Precursor T-Cell Lymphoblastic 
      Leukemia-Lymphoma/genetics/*metabolism/pathology/therapy
MH  - Receptor, Notch1/genetics/*metabolism
MH  - *Signal Transduction
OTO - NOTNLM
OT  - AKT
OT  - Chronic lymphocytic leukemia
OT  - MYC
OT  - Notch
OT  - T-cell acute lymphoblastic leukemia
EDAT- 2018/07/22 06:00
MHDA- 2019/03/21 06:00
CRDT- 2018/07/22 06:00
PHST- 2018/07/22 06:00 [entrez]
PHST- 2018/07/22 06:00 [pubmed]
PHST- 2019/03/21 06:00 [medline]
AID - 10.1007/978-3-319-89512-3_18 [doi]
PST - ppublish
SO  - Adv Exp Med Biol. 2018;1066:355-394. doi: 10.1007/978-3-319-89512-3_18.