Table 2.

Recurrently mutated genes in aCML.

Gene	Chromosomal location	Normal function	Mutations	Clinical implications
SETBP1	18q12.3	It encodes a protein containing a ski homology region, a SET-binding region, and 3 nuclear localization signals. The protein binds to the SET nuclear oncogene which is involved in DNA replication. The SETBP1 protein is thought to control genes involved in developmental processes (e.g. nerve cell migration in the brain during fetal development).	Exon count: 15	Severe anemia and thrombocytopenia
			Nonsense substitution A>C
			Missense substitution A>G	Poor prognosis
			Synonymous substitution A>T
			Inframe deletion C>G
			Frameshift deletion G>A
			Inframe insertion C>A
			Frameshift insertion C>T
			Complex mutation G>C
			c.2602G>A, p.Asp868Asn (sAML, MDS, CMML1/2, CML-BP) c.2608G>A, p.Gly870Ser (sAML, MDS, CMML1/2, CML-BP) c.2640C>A, p.Asp880Glu (sAML) c.2638G>A, p.Asp880Asn (CMML1) c.2612T>C, p.Ile871Thr (sAML, pAML,
ETNK1	12p12.1-p11.2	It catalyzes the first step of the de novo phosphatidylethanolamine biosynthesis pathway, responsible for the phosphorylation of ethanolamine to phosphoethanolamine.	Exon count: 13	Association with altered sensitivity to the AKT kinase inhibitor capivasertib
			Nonsense substitution A>C
			Missense substitution A>G
			Synonymous substitution A>T
			Inframe deletion C>G
			Frameshift deletion G>A
CSF3R	1p34.3	Essential for granulocytic maturation.	Exon Count: 19	Transformation to AML
		Plays a crucial role in the proliferation, differentiation, and survival of cells of the neutrophilic lineage.	Nonsense substitution A>C	Congenital neutropenia
			Missense substitution A>G
			Synonymous substitution A>T
		May function in some adhesion or recognition events at the cell surface.	Inframe deletion C>G
			Frameshift deletion G>A
			Inframe insertion C>A
			Frameshift insertion C>T
			Complex mutation G>C
SRSF2	17q25.1	Necessary for pre-mRNA splicing.	Exon count: 5	Poor prognosis in MDS
		Required for formation of the earliest ATP-dependent splicing complex and interacts with spliceosome components bound to both the 5’- and 3’-splice sites during spliceosome assembly.	Nonsense substitution A>C	No prognosis impact in CMML
			Missense substitution A>G
			Synonymous substitution A>T
			Inframe deletion C>G
			Frameshift deletion G>A
			Inframe insertion C>A
			Frameshift insertion C>T
			Complex mutation G>C
NRAS	1p13.2	Oncogene encoding a membrane protein that shuttles between the Golgi apparatus and the plasma membrane.	Exon count: 7	Associated with altered sensitivity to selumetinib, cediranib, ibrutinib, and dasatinib.
			Nonsense substitution A>C
			Missense substitution A>G
		The protein has intrinsic GTPase activity; it is activated by a guanine nucleotide-exchange factor and inactivated by a GTPase activating protein	Synonymous substitution A>T
			Inframe deletion C>G	Mutations which change amino-acids 12, 13 or 61 enhance the potential of Ras to transform cultured cells and are implicated in a variety of human tumors.
			Frameshift deletion G>A
			Inframe insertion C>A
			Frameshift insertion C>T
			Complex mutation G>C
ASXL1	20q11.21	It encodes a chromatin-binding protein, member of the Polycomb group of proteins involved in transcriptional regulation mediated by ligand-bound nuclear hormone receptors, such as retinoic acid receptors (RARs) and peroxisome proliferator-activated receptor gamma (PPARG).	Exon count: 18	Mutations in ASXL1 are associated with altered sensitivity to 46 drugs among them olaparib, venetoclax, and pevonedistat
			Nonsense substitution A>C
			Missense substitution A>G
			Synonymous substitution A>T
			Inframe deletion C>G
			Frameshift deletion G>A
		It is thought to disrupt chromatin in localized areas, enhancing transcription of certain genes while repressing the transcription of others.	Inframe insertion C>A
			Frameshift insertion C>T
			Complex mutation G>C
TET2	4q24	It plays a key role in active DNA demethylation. It is also involved in the recruitment of the O-GlcNAc OGT to CpG-rich transcription start sites of active genes, thereby promoting histone H2B GlcNAcylation by OGT.	Exon count: 15	Associated with altered sensitivity to bexarotene, Ara-G, tretinoin and VNLG/124.
			Nonsense substitution A>C
			Missense substitution A>G
			Synonymous substitution A>T
			Inframe deletion C>G
			Frameshift deletion G>A
			Inframe insertion C>A
			Frameshift insertion C>T
			Complex mutation G>C

SETBP1, SET Binding Protein 1; sAML, secondary acute myeloid leukemia; MDS, myelodysplastic syndrome; CMML, chronic myelomonocytic leukemia; pAML, primary acute myeloid leukemia; ETNK1, ethanolamine kinase 1; CSF3R, colony stimulating factor 3 receptor; SRSF2, serine and arginine rich splicing factor 2; NRAS, neuroblastoma RAS viral oncogene; ASXL1, Additional Sex Combs Like 1; TET2, Ten-eleven Translocation 2; OGT, O-linked N-acetylglucosamine transferase; Ara-G, 9-β-D- arabinofuranosylguanine, VNLG/124, 4-(butanoyloxymethyl)phenyl(2 E,4 E,6 E,8 E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoate

Frequently encountered mutations are reported in bold.