FLT3 is a receptor tyrosine kinase important in hematopoietic cell proliferation and differentiation. In-frame, FLT3 internal tandem duplications (ITD), which show a wide range of number of nucleotides duplicated and/or inserted (eg, 18-204 bp), affect exons 14 and 15 in the FLT3 juxtamembrane/tyrosine kinase domain and have been reported in 20-30% of patients with acute myeloid leukemia. FLT3 ITDs usually occur in cases of AML with a normal karyotype and but may also occur in cases with chromosome abnormalities including t(15;17) or other cytogenetic groups. Individuals with FLT3 mutations are more likely to have AML than MDS and FLT3 mutations in MDS are associated with a poor prognosis. Functional studies have shown that FLT3 ITDs are ligand-independent, gain-of-function mutations. In addition, activating mutations at codon D835 in exon 20 (A-loop of the tyrosine kinase domain, TKD) of FLT3 have been reported in approximately 7-10% of AML. The FLT3 D835 mutations are also ligand-independent, gain-of-function mutations. FLT3 ITD and D835 mutations tend to occur in a mutually exclusive manner; however, the FLT3 D835 mutation or other mutations in the A-loop(eg, D839, Y842) may occur as an acquired resistance mutation in the setting of patients with FLT3 ITD mutations being treated with targeted therapy. In addition, variants at codon N676 and in exon 17 F691, G697 have been associated with resistance to FLT3 targeted therapy. The presence of FLT3 ITD mutation in young patients with AML and normal cytogenetics is thought to be associated with a poor prognosis. On the other hand, the prognostic significance of the FLT3 D835 and TKD mutations appears less clear. More recently, therapeutic targeting of FLT3 in combination with other chemotherapy is available in certain settings for acute myeloid leukemia with FLT3 ITD or TKD mutations. Lastly, in T cell acute lymphoblastic leukemia, up to 20% of cases have been reported to show a FLT3 mutation (TKD or ITD) and are often associated with an ETP(early T cell precursor) phenotype. In addition, FLT3 mutations have also been reported in up to 15% of B-ALL cases ("Ph-like phenotype") and may also be associated with hyperdiploidy and MLL rearrangement. Targetting FLT3 in acute lymphoblastic leukemia therapy may also be possible in some settings.

This gene is a known cancer gene.

This gene is a known cancer gene.

PIM1 is a member of the PIM family of proteins which are proto-oncogenes, serine-threonine kinases with increased expression in a variety of malignancies. PIM1 expression appears to be up-regulated by STAT5, and has been found to be over-expressed in primary AML blast samples. In particular, PIM1 has associated with FLT3 mediated leukemogenesis in FLT3-ITD AML. PIM1 expression was noted to be 25-fold higher than in FLT3-ITD samples, as compared to wild type FLT3 (WT) AML samples. The PIM kinases, therefore, represent potential therapeutic targets in AML, particularly in those cases harboring FLT3-ITD mutations. According to one study, the small molecule inhibitor of PIM1, AR00459339, alone and in combination with a FLT3 inhibitor (AR00454200), resulted in significant cytotoxicity in FLT3-ITD cell lines and patient samples that strikingly parallels the effects of FLT3 inhibition. A variety of mutations have been reported throughout PIM1 in various types of malignancy including hematopoietic tumors, but PIM1 mutations appear to be extremely rare in acute myeloid leukemia and myelodysplasia.

Mutations of NPM1 have been reported in approximately 25-35% of cases of acute myeloid leukemia (AML). The mutations of NPM1 are frameshift mutations in the C-terminus of the protein that alter the C-terminal amino acid sequence and are associated with aberrant cytoplasmic localization of the protein. NPM1 mutations in AML are typically associated with a normal karyotype and may co-exist with FLT3 mutations. The presence of NPM1 mutations has been associated with improved complete remission rates, but not necessarily overall survival, in multivariate analysis including assessment of the variety of more recently discovered mutations that may be present in AML. In addition, cytogenetically normal AML with mutated NPM1, without FLT3 ITD or mutated DNMT3A, has been considered to be a favorable genetic risk group according to some studies, although other studies suggest that coexistant mutations in IDH1 or IDH2 may be required for the favorable risk effect of NPM1.

BCOR is a ubiquitously expressed nuclear protein that is a transcriptional corepressor important in several cellular processes. Somatic, nonsense and frameshift mutations throughout BCOR have been reported in approximately 7% of chronic myelomonocytic leukemia, 4% of patients with myelodysplastic syndrome(MDS), 4% of primary acute myeloid leukemia and appear to be associated with RUNX1 and DNMT3A mutations . Also, BCOR mutations may be enriched among cases of AML lacking NPM1, CEBPA, FLT3-ITD, IDH1 and MLL-PTD alterations. BCOR mutations tend to be subclonal in MDS, clonal in primary AML and are believed to have significance as loss of function mutations in a tumor suppressor gene that affect the functional allele in male and female patients. The presence of BCOR mutation in patients with MDS and AML has been associated with poorer overall survival according to some studies.

BCOR is a ubiquitously expressed nuclear protein that is a transcriptional corepressor important in several cellular processes. Somatic, nonsense and frameshift mutations throughout BCOR have been reported in approximately 7% of chronic myelomonocytic leukemia, 4% of patients with myelodysplastic syndrome(MDS), 4% of primary acute myeloid leukemia and appear to be associated with RUNX1 and DNMT3A mutations . Also, BCOR mutations may be enriched among cases of AML lacking NPM1, CEBPA, FLT3-ITD, IDH1 and MLL-PTD alterations. BCOR mutations tend to be subclonal in MDS, clonal in primary AML and are believed to have significance as loss of function mutations in a tumor suppressor gene that affect the functional allele in male and female patients. The presence of BCOR mutation in patients with MDS and AML has been associated with poorer overall survival according to some studies.

WT1 encodes for a transcription factor containing an N-terminal transactivation domain and a C-terminal zinc-finger domain necessary for the development of the urogenital system. The precise roles of WT1 in normal and malignant hematopoiesis remain uncertain. New emerging supports a novel role of WT1 in the regulation of epigenetic programs through its interaction with TET proteins in the 5=hydroxymethylation of cytosines. WT1 mutations are found in 6% of acute myeloid leukemia overall, and about 8-13% in cytogenetically normal AML. Higher frequencies are present in biallelic CEBPA mutated acute myeloid leukemia (14%), followed by t(15;17)/PML-RARA (11.0%), and FLT3-ITD (8.5%,). WT1 mutations are associated with younger age in AML. WT1 mutations are typically putative loss of function mutations and most frequently occur in exon 7 or exon 9. About 75% of these mutations are frameshift, and the remaining are missense, nonsense, splice site or inframe indel mutations. In some cases two or more mutations in WT1 may occur. In addition, WT1 mutations may coexist with mutations in NPM1, FLT3, among others. WT1 is overexpressed in the majority of AML, giving rise to the concept that it may act as both a tumor suppressor and oncogene, depending on the context. Several studies showed that WT1 mutations are associated with a worse prognosis in cytogenetically normal acute myeloid leukemia, although one study including patients from three German-Austrian AML study protocols demonstrated no association with overall survival or relapse-free survival. Given its over-expression in AML, clinical trials employing peptide vaccination strategy against WT1 has been ongoing in AML patients.

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.

IDH1 is an enzyme localized to the cytoplasm and peroxisomes and involved in citrate metabolism. Mutations at Arg132 of IDH1 are typically heterozygous mutations and considered gain of function mutations that lead to increased levels of 2-hydroxyglutarate which are believed to alter epigenetic regulation (ie, DNA methylation) in AML. Mutations of IDH1 appear to be mutually exclusive of mutations in TET2, another gene involved in regulation of DNA methylation, and also exclusive of mutations in IDH2. Mutations of IDH1 have been shown to lead to increased DNA methylation in AML. Recurrent missense mutation of Arg 132 in IDH1 has been reported in approximately 5-15% of cases of acute myeloid leukemia and is often associated with a normal karyotype, wild type CEBPA, wild type FLT3 and the presence of NPM1 mutations. In addition, this mutation has been reported in approximately 10-20% of cases with leukemic transformation of myeloproliferative neoplasms and has been reported in less than 5% of chronic phase primary myelofibrosis, less than 5% of myelodysplastic syndrome and rare cases of polycythemia vera, essential thrombocytosis and chronic myelomonocytic leukemia. The prognostic impact of IDH1 mutations in AML appears uncertain, however, in the settings of primary myelofibrosis and polycythemia vera, the presence of IDH1 mutation is independently associated with inferior survival. Mutant IDH1 represents a therapeutic target in some clinical settings.

PTPN11 encodes SHP2, a member of the non-receptor protein tyrosine phosphatase (PTP) family that regulates growth factor and cytokine signaling and plays a key role in the proliferation and survival of hematopoietic cells. PTPN11 mutation is directly associated with the pathogenesis of Noonan syndrome and childhood leukemias. Despite its direct function in protein dephosphorylation, SHP2 plays an overall positive role in transducing signals. Germline and somatic mutations that result in increased activity of PTPN11 have been described in Noonan's syndrome (approximately 50%), juvenile myelomonocytic leukemia (35-42%), pediatric and adult myelodysplasic syndromes (4-10%), B cell acute lymphoblastic leukemia (5-10%), as well as pediatric and adult acute myeloid leukemia (5-10%). These gain of function mutations most often occur as heterozygous missense mutations located in exon 3 (SH2 domain) or exon 13 (phosphatase domain) . Within cases of juvenile myelomonocytic leukemia, mutations of PTPN11 tend to be exclusive of mutations in RAS, CBL and NF-1. PTPN11 mutations in adult AML are associated with a normal karyotype and concurrent NPM1 mutation, but no alteration of the FLT3. In one study, myelodysplastic syndromes with PTPN11 mutations were shown to have a worse overall survival. Small molecule inhibitors of PTPN11 are currently being developed.

Ten-Eleven Translocation-2 (TET2) encodes a dioxygenase that converts 5-methyl-cytosine (5-mC) to 5-hydroxymethyl-cytosine (5-hmC) and promotes DNA demethylation. TET2 is a tumor suppressor gene and loss-of-function via mutations, deletion and IDH1/2 (Isocitrate Dehydrogenase 1 and 2) gene mutations is a common event in myeloid and lymphoid malignancies. TET2 is also present in about 10% of otherwise healthy elderly individuals with clonal hematopoiesis of indeterminate potential (CHIP) and in some patients with unexplained cytopenia but who do not satisfy diagnostic criteria for MDS, so-called clonal cytopenia with undetermined significance (CCUS). Mutations in TET2 occur in 50-60% of chronic myelomonocytic leukemias. 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. TET2 mutations are also found in 20-40% of systemic mastocytosis, 36% of blastic plasamcytoid dendritic cell neoplasm, 12-32% of acute myeloid leukemia, 10-20% of primary myelofibrosis, 10-33% of myelodysplastic syndromes, 10% of myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), 22% of polycythemia vera, and 16% of essential thrombocythemia. TET2 mutations are absent in juvenile myelomonocytic leukemia and show a low prevalence (less than 5%) in pediatric AML. Among lymphoid neoplasms, TET2 mutations are reported in approximately 30% of angioimmunoblastic lymphomas and less than 15 % of other mature T cell lymphomas and mature B cell lymphomas. In general, the mutations in TET2 are typically loss of function variants (frameshift, missense, nonsense mutations) that may be monoallelic or biallelic and occur throughout the gene. TET2 mutations tend to be mutually exclusive of mutations in IDH1/IDH2. TET2 mutations are associated with unfavorable outcomes and shorter survival after hematopoietic stem cell transplantation in patients with myelodysplastic syndrome (PMID: 25092778). In acute myeloid leukemia with wild-type FLT3-ITD and normal karyotype or intermediate-risk cytogenetic abnormalities, TET2 mutations are associated with an unfavorable prognosis.