SON inhibits megakaryocytic differentiation via repressing RUNX1 and the megakaryocytic gene expression program in acute megakaryoblastic leukemia. 2021

Lana Vukadin, and Jung-Hyun Kim, and Eun Young Park, and Joshua K Stone, and Nathan Ungerleider, and Melody C Baddoo, and Hyun Kyung Kong, and Alexander Richard, and Johnny Tran, and Hannah Giannini, and Erik K Flemington, and Ssang-Taek Steve Lim, and Eun-Young Erin Ahn
Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.

A high incidence of acute megakaryoblastic leukemia (AMKL) in Down syndrome patients implies that chromosome 21 genes have a pivotal role in AMKL development, but the functional contribution of individual genes remains elusive. Here, we report that SON, a chromosome 21-encoded DNA- and RNA-binding protein, inhibits megakaryocytic differentiation by suppressing RUNX1 and the megakaryocytic gene expression program. As megakaryocytic progenitors differentiate, SON expression is drastically reduced, with mature megakaryocytes having the lowest levels. In contrast, AMKL cells express an aberrantly high level of SON, and knockdown of SON induced the onset of megakaryocytic differentiation in AMKL cell lines. Genome-wide transcriptome analyses revealed that SON knockdown turns on the expression of pro-megakaryocytic genes while reducing erythroid gene expression. Mechanistically, SON represses RUNX1 expression by directly binding to the proximal promoter and two enhancer regions, the known +23 kb enhancer and the novel +139 kb enhancer, at the RUNX1 locus to suppress H3K4 methylation. In addition, SON represses the expression of the AP-1 complex subunits JUN, JUNB, and FOSB which are required for late megakaryocytic gene expression. Our findings define SON as a negative regulator of RUNX1 and megakaryocytic differentiation, implicating SON overexpression in impaired differentiation during AMKL development.

UI MeSH Term Description Entries
D007947 Leukemia, Megakaryoblastic, Acute An acute myeloid leukemia in which 20-30% of the bone marrow or peripheral blood cells are of megakaryocyte lineage. MYELOFIBROSIS or increased bone marrow RETICULIN is common. Leukemia, Megakaryocytic,Leukemia, Megakaryocytic, Acute,Leukemia, Myeloid, Acute, M7,Megakaryoblastic Leukemia, Acute,Megakaryocytic Leukemia,Megakaryocytic Leukemia, Acute,Myeloid Leukemia, Acute, M7,Acute Megakaryoblastic Leukemia,Acute Megakaryoblastic Leukemias,Acute Megakaryocytic Leukemia,Acute Megakaryocytic Leukemias,Leukemia, Acute Megakaryoblastic,Leukemia, Acute Megakaryocytic,Leukemias, Acute Megakaryoblastic,Leukemias, Acute Megakaryocytic,Leukemias, Megakaryocytic,Megakaryoblastic Leukemias, Acute,Megakaryocytic Leukemias,Megakaryocytic Leukemias, Acute
D008533 Megakaryocytes Very large BONE MARROW CELLS which release mature BLOOD PLATELETS. Megakaryocyte
D002454 Cell Differentiation Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs. Differentiation, Cell,Cell Differentiations,Differentiations, Cell
D004268 DNA-Binding Proteins Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases. DNA Helix Destabilizing Proteins,DNA-Binding Protein,Single-Stranded DNA Binding Proteins,DNA Binding Protein,DNA Single-Stranded Binding Protein,SS DNA BP,Single-Stranded DNA-Binding Protein,Binding Protein, DNA,DNA Binding Proteins,DNA Single Stranded Binding Protein,DNA-Binding Protein, Single-Stranded,Protein, DNA-Binding,Single Stranded DNA Binding Protein,Single Stranded DNA Binding Proteins
D004314 Down Syndrome A chromosome disorder associated either with an extra CHROMOSOME 21 or an effective TRISOMY for chromosome 21. Clinical manifestations include HYPOTONIA, short stature, BRACHYCEPHALY, upslanting palpebral fissures, epicanthus, Brushfield spots on the iris, protruding tongue, small ears, short, broad hands, fifth finger clinodactyly, single transverse palmar crease, and moderate to severe INTELLECTUAL DISABILITY. Cardiac and gastrointestinal malformations, a marked increase in the incidence of LEUKEMIA, and the early onset of ALZHEIMER DISEASE are also associated with this condition. Pathologic features include the development of NEUROFIBRILLARY TANGLES in neurons and the deposition of AMYLOID BETA-PROTEIN, similar to the pathology of ALZHEIMER DISEASE. (Menkes, Textbook of Child Neurology, 5th ed, p213) Mongolism,Trisomy 21,47,XX,+21,47,XY,+21,Down Syndrome, Partial Trisomy 21,Down's Syndrome,Partial Trisomy 21 Down Syndrome,Trisomy 21, Meiotic Nondisjunction,Trisomy 21, Mitotic Nondisjunction,Trisomy G,Downs Syndrome,Syndrome, Down,Syndrome, Down's
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D014162 Transfection The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES. Transfections
D015778 Minor Histocompatibility Antigens Allelic alloantigens often responsible for weak graft rejection in cases when (major) histocompatibility has been established by standard tests. In the mouse they are coded by more than 500 genes at up to 30 minor histocompatibility loci. The most well-known minor histocompatibility antigen in mammals is the H-Y antigen. Histocompatibility Antigens, Minor,Minor Histocompatibility Antigen,Minor Histocompatibility Peptide,Minor Histocompatibility Peptides,Antigen, Minor Histocompatibility,Histocompatibility Antigen, Minor,Histocompatibility Peptide, Minor,Histocompatibility Peptides, Minor,Peptide, Minor Histocompatibility
D015870 Gene Expression The phenotypic manifestation of a gene or genes by the processes of GENETIC TRANSCRIPTION and GENETIC TRANSLATION. Expression, Gene,Expressions, Gene,Gene Expressions
D050676 Core Binding Factor Alpha 2 Subunit A transcription factor that dimerizes with the cofactor CORE BINDING FACTOR BETA SUBUNIT to form core binding factor. It contains a highly conserved DNA-binding domain known as the runt domain. Runx1 is frequently mutated in human LEUKEMIAS. AML1A Protein,AML1B Protein,AML1C Protein,AML1D Protein,Acute Myeloid Leukemia 1 Protein,Acute Myeloid Leukemia 1A Protein,Acute Myeloid Leukemia 1B Protein,Acute Myeloid Leukemia 1C Protein,Acute Myeloid Leukemia 1D Protein,Core-Binding Factor Alpha 2 Protein,Pebp2a2 Protein,Runt-Related Transcription Factor 1,Runx1 Protein,Core Binding Factor Alpha 2 Protein,Runt Related Transcription Factor 1

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