MUTATIONS AT THE TET2 GENE, LET'S STOP THE NOISE!
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WE HAVE EXPLAINED THAT DURING CELL DEVELOPMENT, AND DEPENDING ON LOCATION AND FUNCTION, SOME GENES WILL BE SILENCED.  AND ONE OF THE WAY THE GENE ARE SILENCED IS THROUGH A CERTAIN LEVEL OF METHYLATION. ONE OF THE REGULATOR THAT CHECK LEVEL OF METHYLATION IN HEMATOPOIETIC LINEAGE IS TET2.
IT APPEARS THAT MUTATION OF TET2 HAPPENS AS A RESULT  OF NEOPLASTIC TRANSFORMATION THAT TRIGGERS DEMETHYLATION (DE-SILENCING) OF GENES OF PROLIFERATION,PUSHING  UNCONTROLLED GROWTH.

THAT WHAT'S MUTATION OF TET2 MEANS (READ CAREFULLY DR GRANT COMMENTS)
ONCE THE DEMETHYLATION HAS OCCURRED LOGICALLY THE PRESENCE OF TET2 MUTATIONS SHOULD BE MINIMAL.  ITS PRESENCE MEANS NEW GENES ARE BEING DEMETHYLATED AND MAY EITHER PORTEND TO PERSISTENCE OF PROLIFERATIVE GENES AND THEREFORE ATTEST TO THE NEED OF FURTHER DE- METHYLATING AGENTS.  HYPOMETHYLATING AGENTS SEEMS TO AFFECT METHYLATON OR DISORGANIZE METHYLATION OF PROLIFERATIVE GENES.

LOGICALLY AT THE END OF THE PLANNED CYCLES OF AZACITIDINE OR DECITABINE, TET2 GENE MUTATION PERSISTENCE SHOULD MILITATE AGAINST STOPPING TREATMENT.

HYPOTHETICALLY, TET2 MUTATION MARKS THE FACTS THAT METHYLATION AND THE PROLIFERATIVE PROCESS HAVE BEGUN OR CONTINUE (THE MYELOPROLIFERATIVE PROCESS HAS STARTED), ITS PERSISTENCE     POINT TO NEW METHYLATION OCCURING AND THAT THERAPY WITH THESE AGENTS IS NEEDED STILL.

IN AML OF THE ELDERLY, IT WILL REENFORCE THE NEED FOR THE DECITABINE OPTION OR THAT DECITABINE OR AZACITIDINE SHOULD BE ADDED TO THE REGIMEN IN MAINTENANCE SETTING.

LET'S GO OUT THERE AND VERIFY THIS ASSUMPTION IN PRACTICE

OR CONTINUE THE FOLLOWING NOISE!
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 SMITH ET AL
The encoded protein is involved in myelopoiesis, and defects in this gene have been associated with several myeloproliferative disorders. (GENE RESOURCES)
TET2(mut) were identified in 7.6% of younger adult patients with AML and did not impact the response to therapy and survival. Mutations were mutually exclusive with IDH(mut), which supported recent data on a common mechanism of action that might obscure the impact of TET2(mut) if compared against all other patients with AML.(GAITZIK ET AL)
Tet2 deficiency led to decreased genomic levels of 5hmC and augmented the size of the hematopoietic stem/progenitor cell pool in a cell-autonomous manner.
There was no difference in the frequency of genome-wide aberrations, TET2 expression, or the JAK2V617F 46/1 haplotype between TET2-mutated and nonmutated patients. There was no significant prognostic association between TET2 mutations and World Health Organization subtypes, International Prognostic Scoring System score, cytogenetic status, or transformation to acute myeloid leukemia.

Italian researchers recently determined that mutations in the TET2 gene do not negatively influence the response of patients with myelodysplastic syndromes to treatment with Vidaza. However, they also found that certain modifications to the BCL2L10 gene negatively impacted outcomes following Vidaza treatment.
“TET2 mutations [...] were associated with higher response rates to [Vidaza]. This might help to identify patients at higher probability of response to [Vidaza] and avoid unnecessary burden to unresponsive patients,” said the study’s lead author, Dr. Maria Teresa Voso of the Università Cattolica del Sacro Cuore in Rome, Italy.(LANGHOLTZ)


 Our data indicate that Tet2 has a critical role in regulating the expansion and function of HSCs, presumably by controlling 5hmC levels at genes important for the self-renewal, proliferation, and differentiation of HSCs.(RAO)
  Indeed, while according to the authors TET2 mutations might be involved in the negative regulation of monocyte lineage determination, neither TET2 nor ASXL1 mutations are possibly sufficient in determining the disease establishment. A further interesting observation reported in this paper is that among 14 CMML patients who were tested after progression to acute leukemia (i.e. marrow blasts >20%), only 2 had a TET2 mutation, raising the question as to whether TET2 mutation, when present at diagnosis, might be lost upon leukemic transformation.(ONIDA)

Dr. Grant indicated no relevant conflicts of interest. 
Aberrant methylation of DNA, particularly hypermethylation of tumor suppressor genes, occurs frequently in many cancers, including hematopoietic malignancies. This has prompted the development of agents capable of reversing hypermethylation, such as DNA methyltransferase inhibitors. These agents have yielded encouraging results both alone and in combination with other epigenetic agents (e.g., histone deacetlyase inhibitors) in patients with myelodysplastic syndrome (MDS) and some acute leukemias. However, the endogenous factors regulating the hypermethylated state have not been fully elucidated.


The protein encoded by this gene is a methylcytosine dioxygenase that catalyzes the conversion of methylcytosine to 5-

5-hydroxymethylcytosine. The encoded protein is involved in myelopoiesis, and defects in this gene have been associated with several myeloproliferative disorders TET2 protein is involved in regulating the process of transcription, which is the first step in protein production. Although this protein is found throughout the body, it may play a particularly important role in the production of blood cells from hematopoietic stem cells. These stem cells are located within the bone marrow and have the potential to develop into red blood cells, white blood cells, and platelets. The TET2 protein appears to act as a tumor suppressor, which is a protein that prevents cells from growing and dividing in an uncontrolled way.

TET2 gene alterations are more frequent in chronic myelomonocytic leukemia than in other subgroups of hematopoietic diseases studied so far and could negatively affect the patients’ outcome. The striking association between TET2 gene alterations and monocytosis, already observed in patients with systemic mastocytosis, could indicate a negative role of TET2 in the control of monocytic lineage determination.KOSMIDER ET AL.