ASXL1 regulates epigenetic functions including histone and chromatin modifications. ASXL1 mutations have been reported in 40-50% of chronic myelomonocytic leukemia(CMML), 20% of myelodsyplastic syndromes, 20-35% of primary myelofibrosis, 15% of systemic mastocytosis, 30% of patients with secondary acute myeloid leukemia and 5-10% of primary acute myeloid leukemia. ASXL1 mutations have also been described in CHIP and CCUS. In CMML, missense mutations of ASXL1 appear to be less common (less than 10% of cases). Nonsense and frameshift mutations (but apparently not missense mutations) of ASXL1 have been reported to carry an adverse prognostic impact in cases of chronic myelomonocytic leukemia. In addition, ASXL1 mutations have been associated with adverse outcome in myelodysplasia, primary myelofibrosis and systemic mastocytosis. Among cases of AML, ASXL1 mutations appear to be associated with adverse prognosis in some subtypes of AML according to some, but not all, studies. ASXL1 mutations may coexist with mutations of splicing factor components, TET2 and RUNX1; for example, co-existence of U2AF1 and ASXL1 mutations have been described in CMML and primary myelofibrosis; While in AML, ASXL1 mutations have been reported to be exclusive of NPM1 mutations according to some studies.

ASXL1 regulates epigenetic functions including histone and chromatin modifications. ASXL1 mutations have been reported in 40-50% of chronic myelomonocytic leukemia(CMML), 20% of myelodsyplastic syndromes, 20-35% of primary myelofibrosis, 15% of systemic mastocytosis, 30% of patients with secondary acute myeloid leukemia and 5-10% of primary acute myeloid leukemia. ASXL1 mutations have also been described in CHIP and CCUS. In CMML, missense mutations of ASXL1 appear to be less common (less than 10% of cases). Nonsense and frameshift mutations (but apparently not missense mutations) of ASXL1 have been reported to carry an adverse prognostic impact in cases of chronic myelomonocytic leukemia. In addition, ASXL1 mutations have been associated with adverse outcome in myelodysplasia, primary myelofibrosis and systemic mastocytosis. Among cases of AML, ASXL1 mutations appear to be associated with adverse prognosis in some subtypes of AML according to some, but not all, studies. ASXL1 mutations may coexist with mutations of splicing factor components, TET2 and RUNX1; for example, co-existence of U2AF1 and ASXL1 mutations have been described in CMML and primary myelofibrosis; While in AML, ASXL1 mutations have been reported to be exclusive of NPM1 mutations according to some studies.

This gene is a known cancer gene.

This gene is a known cancer gene.

DNMT3A is a DNA methyltransferase. Recurrent, somatic, heterozygous mutations in DNMT3A have been reported in approximately 18-25% of cases of acute myeloid leukemia (up to 34% of normal karyotype AML), 12-18% of cases of myelodysplastic syndrome, up to 15% of myeloproliferative neoplasms, less than 5% of cases of chronic myelomonocytic leukemia and 15% of cases of adult, eary T cell precursor acute lymphoblastic leukemia. DNMT3A is also one of the most frequently mutated genes in CHIP and CCUS. Mutations in DNMT3A may occur together with mutations in other genes including JAK2, FLT3, IDH1/IDH2, ASXL1, TET2 and NPM1. DNMT3A mutations have been associated with reduced enzymatic activity or altered histone binding, as well as reduced DNA methylation in various genomic regions and altered gene expression in some models. Codon R882 is a hotspot for mutations in DNMT3A. DNMT3A mutations may be associated with adverse prognosis in specific subtypes of AML according to some, but not all studies; the prognostic significance of DNMT3A in AML may depend on patient age, type of DNMT3A mutation (R882 or non-R882 mutation) and the co-existence (or absence) of specific mutations in other genes. DNMT3A mutations may also be associated with adverse prognosis in MDS according to some studies.

GATA2 is a member of the GATA transcription factors which play a role in hematopoiesis. GATA2 mutations in the zinc finger domains have been described in accelerated phase and blasts phase chronic myelogenous leukemia as well as 5-10% of acute myeloid leukemia and familial syndromes with a predisposition to acute myeloid leukemia and myelodysplastic syndromes. Co-existing mutations in ASXL1 have been reported in a subset of patients with mutations in GATA2 and are believed to represent an important step in myeloid transformation, particularly to chronic myelomonocytic leukemia in young female patients. Other reports suggest that in cases of AML, GATA2 mutations have a higher prevalence among cases with biallelic CEBPA mutations and were not observed in cases with monoallelic CEBPA mutations. In general, the GATA2 pathogenic mutations are loss-of-function mutations (nonsense, frameshift, splice site mutations or missense mutations(codons 349-398)) and are believed to result in impairment of granulocyte differentiation. In MDS, GATA2 mutations may be associated with a poor prognosis. If clinical findings and family history are concerning for an inherited disorder, then genetic counseling may be helpful, if clinically indicated.

JAK2 is a non-receptor tyrosine kinase that mediates signaling via the JAK-STAT pathway. The somatic, activating mutation V617F in the pseudokinase domain of JAK2 has been reported in over 90% of patients with polycythemia vera, 40-70% of essential thrombocythemia, 40-60% of primary myelofibrosis and 50% of MDS/MPN with Ring Sideroblasts and Thrombocytosis. JAK2 mutations have also been reported in CHIP. The small percentage of cases of polycythemia vera that do not carry the JAK2 V617F mutation have somatic, activating mutations in JAK2 exon 12 which typically affect the region encompassing codons 536-547 and are in-frame deletions/insertions, duplications of 8-12 amino acids or missense mutations. Mutations in JAK2 are typically mutually exclusive with mutations in the thrombopoietin receptor (MPL) and calreticulin (CALR), but JAK2 mutations may co-exist with mutations in other genes (ie, IDH1, SF3B1, TET2, ASXL1, etc). Ruxolitinib is a JAK2 inhibitor that has been approved for use in patients with intermediate- and high-risk primary myelofibrosis and is under study in other JAK2+ MPNs. Other JAK2 inhibitors (eg, Pacritinib) are also in various stages of study.

CBL (casitas-B-lineage lymphoma) gene mutations have been identified in approximately 15% of chronic myelomonocytic leukemia, 15% of juvenile myelomonocytic leukemia, 15% of secondary AML(from MDS or MDS/MPN overlap syndrome) and rare or absent in polycythemia vera, essential thrombocythemia, primary myelofibrosis, chronic eosinophilic leukemia and MDS. Also, CBL mutations are found in only 1% of de novo acute leukemias and tend to be associated with core binding factor acute myeloid leukemia (AML) among AML cases. CBL is a Ras pathway gene and has been associated with hereditary myeloid disorders. CBL ubiquitinylates and degrades activated receptor and non-receptor tyrosine kinases via the E3-ligase activity of its RING domain. CBL also acts as an adaptor for downstream cell signal transduction, via its tyrosine kinase binding domain. Most variants of the CBL protein are missense substitutions in the zinc binding RING domain (amino acids 366-420) (exons 8-9) that abrogate CBL ubiquitin ligase activity but retain other functions. Pathogenic mutations are believed to be oncogenic by a variety of potential mechanisms including increased Ras pathway activation, aberrant phosphoSTAT5 and/or increased KIT expression in different cellular contexts. Occasionally, two CBL mutations may be present or CBL mutations may be associated with uniparental disomy. In addition, CBL mutations may occur together with mutations in other genes ( RUNX1, ASXL1, TET2 or EZH2 ). According to some studies, mutations of CBL may be associated with reduced overall survival in MDS.

SRSF2 is a member of the serine/arginine-rich family of pre-mRNA splicing factors, which constitute part of the spliceosome. It interacts with other spliceosomal components bound to both the 5- and 3-splice sites during spliceosome assembly. SRSF2 mutations typically occur as missense mutations at Pro95. SRSF2 mutations have been reported in approximately 40% of cases of chronic myelomonocytic leukemia, but they may not have prognostic significance in that entity. Comutation of TET2 and SRSF2 was highly predictive of a myeloid neoplasm characterized by myelodysplasia and monocytosis, including but not limited to, chronic myelomonocytic leukemia. In addition, SRSF2 mutations have been reported in approximately 15-20% of cases of myelodysplastic syndrome. SRSF2 mutations have also been described in 5-20% of patients with acute myeloid leukemia and appear to be enriched among AML patients with reduced blast counts. SRSF2 has been found to be mutated in approximately 10% of cases of primary myelofibrosis where mutations may occur together with mutations in JAK2, MPL, TET2, CBL, ASXL1, EZH2, IDH1/2. SRSF2 mutations are also present in 8% of blastic plasmacytoid dendritic cell neoplasm and 3% of polythemia vera. SRSF2 mutations tend to be (although are not entirely) exclusive of mutations in other splicing factor components. SRSF2 mutations are associated with a poor prognosis in myelodysplastic syndrome (NCCN Guidelines for Myelodysplastic Syndromes), primary myelofibrosis, polycythemia vera, and KIT D816V-mutated advanced systemic mastocytosis. SRSF2 mutations are also reported to be highly specific for secondary acute myeloid leukemia, and may also be helpful in identifying a subset of elderly patients with de novo acute myeloid leukemia and therapy-related AML with worse clinical outcomes.

SETBP1 encodes a protein which is believed to inhibit PP2A phosphatase activity through SET stabilization. In addition, SETBP1 binds to gDNA in AT-rich promoter regions, causing activation of a network of development genes through recruitment of a HCF1/KMT2A/PHF8 epigenetic complex. Heterozygous, somatic, missense mutations are predominantly hot-spot mutations within the SKI homologous region in exon 4, which result in the functional loss of the degron motif responsible for the short half-life of the protein. Therefore, these mutations result in an increased half-life and accumulation of the mutated SETBP1, and thus increased inhibition of the oncosupressor PP2A through the SETBP1-SET-PP2A axis. In addition, mutations in SETBP1 potentially deregulate gene transcription mediated by SETBP1. SETBP1 mutations have been described in approximately 25% of atypical chronic myelogenous leukemia, 30% of juvenile myelomonocytic leukemia, 17% of secondary acute myeloid leukemia, 13% of myeloproliferative/myelodysplastic syndrome with ring sideroblasts and thrombocytosis, and 5-15% of chronic myelomonocytic leukemia. SETPB1 mutations appear to be rare (< 5%) or absent among cases of primary acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndromes, myeloproliferative neoplasms and chronic lymphocytic leukemia. SETBP1 mutations may be seen together with mutations in other genes such as ASXL1. Mutated SETBP1 provides supportive evidence for the diagnosis of atypical chronic myeloid leukemia, BCR-ABL1-negative in the 2016 revision of the WHO classification.SETBP1 mutations are associated with disease progression in myelodysplastic syndrome (NCCN Guidelines for Myelodysplastic Syndromes), and unfavorable prognosis in chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, atypical chronic myeloid leukemia, and MDS/MPN with ring sideroblasts associated and thrombocytosis.