PMID- 21326611
OWN - NLM
STAT- MEDLINE
DCOM- 20110901
LR  - 20211020
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 6
IP  - 2
DP  - 2011 Feb 4
TI  - Transient responses to NOTCH and TLX1/HOX11 inhibition in T-cell acute 
      lymphoblastic leukemia/lymphoma.
PG  - e16761
LID - 10.1371/journal.pone.0016761 [doi]
LID - e16761
AB  - To improve the treatment strategies of T-cell acute lymphoblastic 
      leukemia/lymphoma (T-ALL), further efforts are needed to identify therapeutic 
      targets. Dysregulated expression of HOX-type transcription factors occurs in 
      30-40% of cases of T-ALL. TLX1/HOX11 is the prototypical HOX-type transcription 
      factor. TLX1 may be an attractive therapeutic target because mice that are 
      deficient in TLX1 are healthy. To test this possibility, we developed a 
      conditional doxycycline-regulated mouse model of TLX1-initiated T-ALL. TLX1 
      induced T-ALL after  approximately 5-7 months with penetrance of 15-60%. Similar to human 
      TLX1-type T-ALLs, the TLX1-induced tumors were arrested at the cortical stage of 
      T-cell development and acquired activating NOTCH1 mutations. Inhibition of NOTCH 
      signaling abrogated growth of cell lines derived from the TLX1-induced tumors. 
      NOTCH inhibition also transiently delayed leukemia progression in vivo. 
      Suppression of TLX1 expression slowed the growth of TLX1 tumor cell lines. 
      Suppression of TLX1 in vivo also transiently delayed leukemia progression. We 
      have shown that TLX1 functions as a T-cell oncogene that is active during both 
      the induction and the maintenance phases of leukemia. However, the effect of 
      suppressing NOTCH or TLX1 was transient. The tumors eventually "escaped" from 
      inhibition. These data imply that the biological pathways and gene sets impacted 
      by TLX1 and NOTCH have largely lost their importance in the fully established 
      tumor. They have been supplanted by stronger oncogenic pathways. Although TLX1 or 
      NOTCH inhibitors may not be effective as single agents, they may still contribute 
      to combination therapy for TLX1-driven acute leukemia.
FAU - Rakowski, Lesley A
AU  - Rakowski LA
AD  - Division of Hematology-Oncology, Department of Internal Medicine, University of 
      Michigan, Ann Arbor, Michigan, United States of America.
FAU - Lehotzky, Erica A
AU  - Lehotzky EA
FAU - Chiang, Mark Y
AU  - Chiang MY
LA  - eng
GR  - K08 CA120544/CA/NCI NIH HHS/United States
GR  - P30 CA046592/CA/NCI NIH HHS/United States
PT  - Evaluation Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110204
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Homeodomain Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Receptor, Notch1)
RN  - 143275-75-6 (TLX1 protein, human)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/administration & dosage/pharmacology/*therapeutic use
MH  - Bone Marrow Transplantation/methods
MH  - Cells, Cultured
MH  - Disease Progression
MH  - Gene Expression Regulation, Leukemic/drug effects
MH  - Homeodomain Proteins/*antagonists & inhibitors/genetics/metabolism/physiology
MH  - Humans
MH  - Immunotherapy, Adoptive/methods
MH  - Leukemia-Lymphoma, Adult T-Cell/*drug therapy/pathology/therapy
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Molecular Targeted Therapy
MH  - Proto-Oncogene Proteins/*antagonists & inhibitors/genetics/metabolism/physiology
MH  - Receptor, Notch1/*antagonists & inhibitors/metabolism/physiology
MH  - Time Factors
PMC - PMC3033898
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2011/02/18 06:00
MHDA- 2011/09/02 06:00
PMCR- 2011/02/04
CRDT- 2011/02/18 06:00
PHST- 2010/10/12 00:00 [received]
PHST- 2010/12/29 00:00 [accepted]
PHST- 2011/02/18 06:00 [entrez]
PHST- 2011/02/18 06:00 [pubmed]
PHST- 2011/09/02 06:00 [medline]
PHST- 2011/02/04 00:00 [pmc-release]
AID - PONE-D-10-03508 [pii]
AID - 10.1371/journal.pone.0016761 [doi]
PST - epublish
SO  - PLoS One. 2011 Feb 4;6(2):e16761. doi: 10.1371/journal.pone.0016761.