Inherited mutations Rare
missense and other
loss of function mutations in ETV6 cause thrombocytopenia 5, an
autosomal dominant familial disease characterized by variable
thrombocytopenia (
blood platelet counts from 5% to 90% of normal), mild to modest bleeding tendencies, and
bone marrow biopsy findings of abnormal appearing megakaryocytes (i.e. nuclei with fewer than the normal number of lobulations) and red cell
macrocytosis. Thrombocytopenia 5 is associated with an increased incidence of developing hematological (e.g.
chronic myelomonocytic leukemia,
acute myelocytic leukemia, B cell
acute lymphoblastic leukemia, mixed phenotype acute leukemia,
Myelodysplastic syndrome, and
multiple myeloma) and non-hematological (e.g. skin and colon) cancers as well as non-malignant diseases such as refractory
anemia myopathies, and
gastroesophageal reflux disease. Two unrelated kindreds were found to have
autosomal dominant inherited mutations in the
ETV6 gene, one family with a germline DNA substitution termed L349P that lead to replacing leucine with proline at amino acid 349 in the DNA binding domain of the ETV6, the second, termed N385fs, in germline DNA caused the lose of five base pairs
ETV6 and a truncated ETV6 protein. Both mutant proteins failed to enter cell nuclei normally and had a reduced capacity to target genes regulated by the normal ETV6 protein. Afflicted members of these families had low platelet counts (i.e. thrombocytopenia) and
acute lymphoblastic leukemia. Fifteen members of the two kindreds had thrombocytopenia, five of whom also had acute lymphoblastic leukemia. The L249P kindred also had one family member with
renal cell carcinoma and another family member with
Duodenal cancer. The relationship of these two cancers to the L249P mutation has not been investigated. In all events these two familial thrombocytopenia syndromes appear distinctly different than the thrombocytopenia 5 syndrome.
Treatment Family members with thrombocytopenia 5 need to be regularly monitored with
complete blood count and
blood smear screenings to detect the early changes brought on by the malignant transformations of this disease into hematological neoplasms. Patients who developed these transformations have generally been treated similarly to patients who have the same hematological neoplasms but on a non-familial basis. Patients developing non-malignant hematological or non-hematological solid tumor manifestations of thrombocytopenia 5 are also treated like to patients with the same but no-familial disease.
Hematological malignancies The following table lists the more frequently occurring genes to which ETV6 fuses, the function of these genes, these genes' chromosomal locations, the notation designating the most common sites of the translocations of these fused genes, and the malignancies resulting from these translocations. These translocation mutations commonly occur in
pluripotent hematopoietic stem cells that differentiate into various types of mature hematological cells. Consequently, a given mutation may lead to various types of
hematological malignancies. In addition to the fusion gene-producing translocations given in the table,
ETV6 has been reported to fuse with other genes in very rare cases (i.e. 1-10 published reports). These translocations lead to one or more of the same types of hematological malignancies listed in the table. Thus, the
ETV6 gene reportedly forms translocation-induced fusion genes with:
f) transcriptional coactivator for nuclear hormone receptors gene
NCOA2;
f) Immunoglobulin heavy chain gene IGH;
g) enzyme genes
TTL (adds and removes tyrosine residues on
α-tubulin),
GOT1 (an
Aspartate transaminase), and
ACSL6 (a
Long-chain-fatty-acid—CoA ligase);
h) transporter gene
ARNT (binds to
ligand-bound
aryl hydrocarbon receptor to aid in its movement to the nucleus where it promotes the expression of genes involved in xenobiotic metabolism);
i) unknown function genes
CHIC2,
MDS2,
FCHO2 and
BAZ2A.; and
j) non-annotated gene
STL (which has no long
open reading frame). At least 9
frameshift mutations in the'
ETV6 gene have been associated with ~12% of adult T cell
Acute lymphoblastic leukemia cases. These mutations involve insertions or deletions in the gene that lead to its encoding a truncated and therefore inactive ETV6 protein. These mutations commonly occur alongside mutations in another oncogene,
NOTCH1, which is associated with T cell acute lymphoblastic lymphoma quite independently of ETV6. It is suggested that suppressor mutations in the
ETV6 gene may be a contributing factor in the development ant/or progression of this leukemia type.
Treatment Patients developing hematological malignancies secondary to the
ETV6 gene fusion to receptor tyrosine kinases and non-receptor tyrosine kinases may be sensitive to therapy with
tyrosine kinase inhibitors. For example, patients with clonal eosinophilias due to
PDGFRA or
PDGFRB fusion genes experience long-term, complete remission when treated with are highly sensitive tyrosine kinase inhibitor,
gleevec. Clinical trials have found that the first generation tyrosine kinase inhibitors
sorafenib,
sunitinib,
midostaurin,
lestaurtinib have shown some promise in treating
acute myelogenous leukemia associated with the
FLT3-TKI fusion gene; the second generation tyrosine kinase inhibitors
quizartinib and
crenolanib which are highly selective in inhibiting the FLT3 protein, have shown significant promise in treating relapsed and refractory acute myelogenous leukemia related to the
FLT3-TKI fusion gene. One patient with
ETV6-FLT3-related myeloid/lymphoid neoplasm obtained a short term remission on sunitinib and following relapse, on sorafenib suggesting that the cited FLT3 protein tyrosine kinase inhibitors may prove useful for treating
ETV6-FLT-related hematologic malignancies. Two patients suffering hematologic malignancies related to
PCM1-JAK2 or
BCR-JAK2 fusion genes experienced complete and cytogenetic remissions in response to the tyrosine kinase inhibitor
ruxolitinib; while both remissions were short-term (12 months), these results suggest that tyrosine kinase inhibitors that target JAK2 may be of some use for treating hematologic malignancies associated with
ETV6-JAK2 fusion stems. It is possible that hematological malignancies associated with
ETV6 gene fusions to either the
SYK or
FRK tyrosine kinase genes may someday be shown susceptible to tyrosine kinase inhibitor therapy. However, children with
ETV6-RUNX1-associated
acute lymphoblastic leukemia are in an especially good-risk subgroup and therefore have been almost uniformly treated with standard-risk
chemotherapy protocols. Hematological malignancies associated with
ETY6 gene fusions to other transcription factor genes appear to reflect a loss or gain in function of
ETV6 and/or the other genes in regulating expression of their target genes; this results in the formation or lack of formation of products which influence cell growth, proliferation, and/or survival. In vitro studies of
ETV6-RUNX, ETV6-MN1, ETV6-PER1, and
ETV6-MECOM fusion genes support this notion. Thus, the
ETV6-MECOM fusion gene is overexpressed because it is driven by the
promoter derived from
ETV6 The chimeric protein products of
ETV6 gene fusions with
ARNT, TTL, BA22A, FCHO2, MDS2, and
CHIC2 likewise lack ETV6 protein's transcription factor activity.
Treatment The treatment of
ETV6 gene-associated solid tumors has not advanced as far as that for
ETV6 gene-associated hematological malignancies. It is proposed that
tyrosine kinase inhibitors with specificity for NTRK3's tyrosine kinase activity in
ETV6-NTRK3 gene-associated solid tumors may be of therapeutic usefulness.
Entrectinib, a pan-NTRK as well as an
ALK and
ROS1 tyrosine kinase inhibitor has been found useful in treating a single patient with
ETV6-NRTK3 fusion gene-associated
mammary analogue secretory carcinoma and lends support to the clinical development of NTRK3-directed tyrosine kinase inhibitors to treat ETV6-NTRK3 fusion protein associated malignancies. == See also ==