Core transcriptional regulatory circuit controlled by the TAL1 complex in human T cell acute lymphoblastic leukemia.
The oncogenic transcription factor TAL1/SCL is aberrantly expressed in over 40% of cases of human T cell acute lymphoblastic leukemia (T-ALL), emphasizing its importance in the molecular pathogenesis of T-ALL. Here we identify the core transcriptional regulatory circuit controlled by TAL1 and its regulatory partners HEB, E2A, LMO1/2, GATA3, and RUNX1. We show that TAL1 forms a positive interconnected autoregulatory loop with GATA3 and RUNX1 and that the TAL1 complex directly activates the MYB oncogene, forming a positive feed-forward regulatory loop that reinforces and stabilizes the TAL1-regulated oncogenic program. One of the critical downstream targets in this circuitry is the TRIB2 gene, which is oppositely regulated by TAL1 and E2A/HEB and is essential for the survival of T-ALL cells.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Takaomi
T
Sanda
Lee N
LN
Lawton
M Inmaculada
MI
Barrasa
Zi Peng
ZP
Fan
Holger
H
Kohlhammer
Alejandro
A
Gutierrez
Wenxue
W
Ma
Jessica
J
Tatarek
Yebin
Y
Ahn
Michelle A
MA
Kelliher
Catriona H M
CH
Jamieson
Louis M
LM
Staudt
Richard A
RA
Young
A Thomas
AT
Look
D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D015973:Gene Expression Regulation, Leukemic; D053263:Gene Regulatory Networks / Q000235:genetics*; D052138:Genes, Neoplasm / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000145:classification / Q000235:genetics* / Q000473:pathology; D011485:Protein Binding / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology
D051792:Basic Helix-Loop-Helix Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C067143:TAL1 protein, human