CHIP Flashcards
Epigenetic regulator-group CHIP mutations
DNMT3A
TET2
ASXL1
These 3 mutations make up 80% of driver mutations of CHIP
DNA repair-group CHIP mutations
TP53
PPM1D
Splicosome-group CHIP mutations
SF3B1
SRSF2
Tyrosine kinase-group CHIP mutations
JAK2
Requirements for a diagnosis of CHIP
1) Evidence of clonal hematopoiesis with candidate driver mutation (DNMT3A, TET2, ASXL3, JAK2, PPM1D, TP53, SF3B1, SRSF2)
2) Normal cellular morphology
3) Candidate driver mutation represents >2% VAF of peripheral blood
4) Does not meet the diagnostic criteria of another hematologic disorder
DNMT3A
Most commonly mutated gene in CHIP
Methyltransferase enzyme that catalyzes DNA methylation at CpG sites. Pathogenic mutations are LoF variants which result in enhanced HSC self-renewal, promote transcription of multipotency genes (RUNX1, GATA3, PBX1, CDKN1A), and suppress cell differentiation programs (FLK2, IKAROS, SFPI1, MEF2C).
R882(C/H) is the most frequent variant.
TET2
Second most commonly mutated gene in CHIP
Encodes a DNA demethylase that hydroxylates methylated cytosines, producing hmC markers with distinct epigenetic functions.
TET2 LoF enhances HSC self-renewal and biases cell differentiation towards the myeloid lineage, and particularly to macrophages. 50% of cases of CMML also have a TET2 mutation.
Of note, IDH1/2 mutations are exclusive with TET2 mutations in AML, but NOT in AITL, and IDH is a known regulator of TET2.
IDH1/2-DNMT3-DNMT1-TET2-ASXL1 system
DNA methylation (mC) is introduced at cytosines by DNA methyltransferases -3A and -3B (DNMT3A and DNMT3B) and maintained by DNMT1. The Ten-Eleven-Translocation (TET) family of proteins (TET1,-2,-3) can oxidize mC to hydroxymethylcytosine (hmC), a mark that is differentialy regulated by DNMT1 compared to mC. IDH-1/2 play the role of regulators of this pathway. ASXL1 is thought to be downstream of TET2.
TET2-dependent hmC is an important activator of HSC self-renewal genes while TET2-dependent hmC and DNMT3A-dependent mC cooperate to repress cell differentiation pathways.
The exact mechanisms by which this system operates are still being elucidated.
ASXL1
Third most commonly mutated gene in CHIP
The ASXL1 gene product regulates polycomb-mediated transcriptional repression of HOX genes.
LoF results in clonal hematopoiesis, and also results in shift towards myeloid differentiation. Like TET2, it is also found in CMML. Of note, TET2 and ASXL1 mutations are not found to be mutually exclusive.
The exact mechanisms remain unclear.
IDH1 and IDH2
IDH1 is cytoplasmic, while IDH2 is mitochondrial
Catalytic arginines are most commonly mutated (R132 in IDH1, R140 and R172 in IDH2).
The epigenetic regulatory effects of IDH isozymes are primarily dependent upon their regulation of alpha-ketoglutarate, which is necessary for aKH dioxygenase function - including EGLN prolyl hydroxylases and TET-family proteins.
Polycomb repressor complex
Family of HOX gene regulators which, along with the antagonistic Trithorax-group regulators, control cell differentiation and body planning.
Humans have two PRCs: PRC1 and PRC2. PRC2 acts as epigenetic silencers which methylate histones via the enzymatic subunits EZH1 and EZH2. PRC1 functions as a ubiquitin ligase for histones via its subunits RING1A and RING1B.
