How TET2 Plays A Pivotal Role In CMML

Chronic myelomonocytic leukemia (CMML) is a type of blood cancer where abnormal monocytes (a type of white blood cell) growth occurs in the bone marrow. These changes are often related to specific mutations in a certain gene called TET2. 

What Is TET2?

TET2 is the name of a gene that produces a protein called tet methylcytosine dioxygenase 2. When this protein functions properly, it can be a tumor suppressor, which prevents cells from growing and dividing uncontrollably. It is found throughout the body and is important in developing blood cells. It is predominantly seen in the spleen and bone marrow.

Mutated TET2 Impact 

Mutations in TET2 are seen in approximately 30% of people with myeloid malignancies, such as myelodysplastic syndromes, chronic myelomonocytic leukemia, and myeloproliferative neoplasms. They are also the most frequent mutations identified in peripheral T-cell lymphomas. They are a significant genetic factor contributing to the development of CMML, often associated with a poorer prognosis for patients. 

A recent study discovered that the mutated TET2 changes the body’s RNA, altering the structure and pathway of this protein. This leads to an open environment that allows blood cancer cells to grow. The study uncovered that MBD6 is a great target for treating myeloid malignancies with the TET2 mutation.

Almost a decade ago, it was discovered that 10% of people aged 70 and older who have the TET2 mutation (and others) can develop clonal hematopoiesis of indeterminate potential (CHIP). These patients have a higher possibility of developing myeloid cancer and cardiovascular diseases.

How Are CMML And TET2 Connected?

Mutations in the TET2 gene are commonly found in CMML patients, often occurring alongside other genetic abnormalities like ASXL1 and RUNX1 mutations. When TET2 is mutated, its ability to remove methyl from the DNA is impaired, leading to abnormal gene expression and uncontrolled cell growth, contributing to the development of CMML. The presence of a TET2 mutation in a CMML patient can be used as a prognostic marker, as it is often linked to a more aggressive disease course and poorer overall survival. 

Conclusion

TET2 plays a pivotal role in the development of CMML. Understanding what role mutations play in a disease, treatment can be tailored and specific to the patient and improving the overall efficacy of therapy.

“This study is a turning point potentially leading to the exploration of several players within this pathway that could be targets for therapeutic intervention.” - Mingjiang Xu, molecular medicine professor at the Joe R. and Teresa Lozano Long School of Medicine.

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Source: 

• Gene-mutation pathway discovery paves way for targeted blood cancers therapies