The role of the proto-oncogene ETS2 in acute megakaryocytic leukemia biology and therapy.
Acute myeloid leukemia (AML) in Down syndrome (DS) children has several unique features including a predominance of the acute megakaryocytic leukemia (AMkL) phenotype, higher event-free survivals compared to non-DS children using cytosine arabinoside (ara-C)/anthracycline-based protocols and a uniform presence of somatic mutations in the X-linked transcription factor gene, GATA1. Several chromosome 21-localized transcription factor oncogenes including ETS2 may contribute to the unique features of DS AMkL. ETS2 transcripts measured by real-time RT-PCR were 1.8- and 4.1-fold, respectively, higher in DS and non-DS megakaryoblasts than those in non-DS myeloblasts. In a doxycycline-inducible erythroleukemia cell line, K562pTet-on/ETS2, induction of ETS2 resulted in an erythroid to megakaryocytic phenotypic switch independent of GATA1 levels. Microarray analysis of doxycycline-induced and doxycycline-uninduced cells revealed an upregulation by ETS2 of cytokines (for example, interleukin 1 and CSF2) and transcription factors (for example, TAL1), which are key regulators of megakaryocytic differentiation. In the K562pTet-on/ETS2 cells, ETS2 induction conferred differences in sensitivities to ara-C and daunorubicin, depending on GATA1 levels. These results suggest that ETS2 expression is linked to the biology of AMkL in both DS and non-DS children, and that ETS2 acts by regulating expression of hematopoietic lineage and transcription factor genes involved in erythropoiesis and megakaryopoiesis, and in chemotherapy sensitivities.
Ge
Y
Y
Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA.
LaFiura
K M
KM
Dombkowski
A A
AA
Chen
Q
Q
Payton
S G
SG
Buck
S A
SA
Salagrama
S
S
Diakiw
A E
AE
Matherly
L H
LH
Taub
J W
JW
D000208:Acute Disease; D002454:Cell Differentiation / Q000235:genetics; D002648:Child; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D003561:Cytarabine / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D004314:Down Syndrome / Q000150:complications; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015672:Erythroid Precursor Cells / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000502:physiology; D018628:Gene Dosage; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D020014:K562 Cells / Q000187:drug effects / Q000378:metabolism; D007947:Leukemia, Megakaryoblastic, Acute / Q000209:etiology / Q000235:genetics; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics; D008533:Megakaryocytes / Q000187:drug effects / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000090063:Proto-Oncogene Mas; D050787:Proto-Oncogene Protein c-ets-2 / Q000502:physiology*; D034061:Thrombopoiesis / Q000235:genetics
C494069:ETS2 protein, human; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; C000715470:MAS1 protein, human; D009363:Neoplasm Proteins; D000090063:Proto-Oncogene Mas; D050787:Proto-Oncogene Protein c-ets-2; D003561:Cytarabine; D003630:Daunorubicin