H2.0-like homeobox regulates early hematopoiesis and promotes acute myeloid leukemia.
Homeobox domain-containing transcription factors are important regulators of hematopoiesis. Here, we report that increased levels of nonclustered H2.0-like homeobox (HLX) lead to loss of functional hematopoietic stem cells and formation of aberrant progenitors with unlimited serial clonogenicity and blocked differentiation. Inhibition of HLX reduces proliferation and clonogenicity of leukemia cells, overcomes the differentiation block, and leads to prolonged survival. HLX regulates a transcriptional program, including PAK1 and BTG1, that controls cellular differentiation and proliferation. HLX is overexpressed in 87% of patients with acute myeloid leukemia (AML) and independently correlates with inferior overall survival (n = 601, p = 2.3 × 10(-6)). Our study identifies HLX as a key regulator in immature hematopoietic and leukemia cells and as a prognostic marker and therapeutic target in AML.
Department of Cell Biology and Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Masahiro
M
Kawahara
Ashley
A
Pandolfi
Boris
B
Bartholdy
Laura
L
Barreyro
Britta
B
Will
Michael
M
Roth
Ujunwa C
UC
Okoye-Okafor
Tihomira I
TI
Todorova
Maria E
ME
Figueroa
Ari
A
Melnick
Constantine S
CS
Mitsiades
Ulrich
U
Steidl
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D016923:Cell Death; D002454:Cell Differentiation / Q000235:genetics; D002999:Clone Cells; D015536:Down-Regulation / Q000235:genetics; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology*; D051379:Mice; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D016019:Survival Analysis; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome / Q000235:genetics
D018952:Antigens, CD34; C084058:HLX protein, human; D018398:Homeodomain Proteins; D014157:Transcription Factors; D019009:Proto-Oncogene Proteins c-kit