内科: オープンアクセス
オープンアクセス

概要

Hematologic Oncology 2018: Targeting casein kinase II (CK2) for treatment of high risk leukemia - Chandrika Gowda - Pennsylvania State University

Chandrika Gowda

Acute lymphoblastic leukemia (ALL) is the most common cancer in children and accounts for highest death rate among children aged 10-19 years. Current treatment for relapsed high risk ALL involves augmented chemotherapy, hematopoietic stem cell transplant and radiation therapy which adds to the morbidity of already sick children. Recent genome-wide studies of leukemic blasts have detected genetic lesions such as deletions or mutations in IKZF1. Alterations in IKZF1 have proven to be an indicator of inferior outcome in patients with high-risk ALL. Ikaros (IKZF1) functions as a master regulator of hematopoiesis and a tumor suppressor in ALL. Ikaros binds to the upstream regulatory elements of its target genes and regulates their transcription via chromatin remodeling. Casein kinase II (CK2) is a pro-oncogenic protein which is overexpressed in various cancers including leukemia. Functional experiments showed that CK2-mediated phosphorylation of Ikaros, regulates Ikaros’ DNA binding affinity, subcellular localization, and protein stability. Dysregulation of several biological pathways in children with high-risk B-ALL results from CK2 overexpression and impaired Ikaros function. Targeted inhibition of CK2 restores Ikaros tumor suppressor function in high-risk B-ALL even in cases with single allele Ikaros deletion. Treatment with the selective CK2 inhibitor, CX4945 exhibits an anti-leukemic effect in primary xenograft models of high-risk B-ALL. Further studies use precision medicine approaches (targeting specific pathways and/or functional defects) to develop novel drug combinations to target these dysregulated pathways by inhibiting CK2 and restoring Ikaros tumor suppressor function as well as using a specific inhibitor of the signaling pathway. Much of the time, the reason is obscure. Hereditary hazard components may incorporate Down disorder, Li-Fraumeni condition, or neurofibromatosis type 1. Natural hazard elements may incorporate critical radiation introduction or earlier chemotherapy. Proof with respect to electromagnetic fields or pesticides is hazy. Some speculate that a strange invulnerable reaction to a typical disease might be a trigger. The basic system includes numerous hereditary transformations that outcomes in fast cell division. The exorbitant youthful lymphocytes in the bone marrow meddle with the creation of new red platelets, white platelets, and platelets. Determination is regularly founded on blood tests and bone marrow assessment. Everything is regularly rewarded at first with chemotherapy planned for realizing reduction. This is then trailed by further chemotherapy commonly over various years. Extra medicines may incorporate intrathecal chemotherapy or radiation treatment whenever spread to the mind has happened. Undeveloped cell transplantation might be utilized if the ailment repeats adhering to standard treatment. Extra medicines, for example, immunotherapy are being considered. The destructive cell in ALL is the lymphoblast. Typical lymphoblasts form into develop, contamination battling B-cells or T-cells, additionally called lymphocytes. Signs in the body control the quantity of lymphocytes so neither too few nor too many are made. Taking all things together, both the typical advancement of certain lymphocytes and the command over the quantity of lymphoid cells become faulty. ALL rises when a solitary lymphoblast increases numerous transformations to qualities that influence platelet improvement and multiplication. In youth ALL, this procedure starts at origination with the legacy of a portion of these qualities. These qualities, thusly, increment the hazard that more transformations will happen in creating lymphoid cells. Certain hereditary conditions, as Down Syndrome, have a similar impact. Natural hazard factors are likewise expected to help make enough hereditary transformations to cause sickness. Proof for the job of the earth is found in youth ALL among twins, where just 10–15% of both hereditarily indistinguishable twins get ALL. Since they have similar qualities, diverse natural exposures clarify why one twin gets ALL and different doesn’t. Baby ALL is an uncommon variation that happens in babies short of what one year old. KMT2A (earlier MLL) quality revisions are generally normal and happen in the undeveloped organism or embryo before birth. These revisions bring about expanded articulation of platelet improvement qualities by advancing quality interpretation and through epigenetic changes. As opposed to youth ALL, natural elements are not thought to assume a noteworthy job. Beside the KMT2A adjustment, just a single additional transformation is commonly found. Natural exposures are not expected to help make more transformations.