Weekly articles of interest related to cytogenetics selected by our principal investigator, student researchers, or other affiliates.
Article: Síndrome de trisomía 21
Abstract: Fusions of the Runt-related transcription factor 1 (RUNX1) with different partner genes have been associated with various hematological disorders. Interestingly, the C-terminally truncated form of RUNX1 and RUNX1 fusion proteins are similarly considered important contributors to leukemogenesis. Here, we describe a 59-year-old male patient who was initially diagnosed with acute myeloid leukemia, inv(16)(p13;q22)/CBFB-MYH11 (FAB classification M4Eo). He achieved complete remission and negative CBFB-MYH11 status with daunorubicin/cytarabine combination chemotherapy but relapsed 3 years later. Cytogenetic analysis of relapsed leukemia cells revealed CBFB-MYH11 negativity and complex chromosomal abnormalities without inv(16)(p13;q22). RNA-seq identified the glutamate receptor, ionotropic, kinase 2 (GRIK2) gene on 6q16 as a novel fusion partner for RUNX1 in this case. Specifically, the fusion of RUNX1 to the GRIK2 antisense strand (RUNX1-GRIK2as) generated multiple missplicing transcripts. Because extremely low levels of wild-type GRIK2 were detected in leukemia cells, RUNX1-GRIK2as was thought to drive the pathogenesis associated with the RUNX1-GRIK2 fusion. The truncated RUNX1 generated from RUNX1-GRIK2as induced the expression of the granulocyte colony-stimulating factor (G-CSF) receptor on 32D myeloid leukemia cells and enhanced proliferation in response to G-CSF. In summary, the RUNX1-GRIK2as fusion emphasizes the importance of aberrantly truncated RUNX1 in leukemogenesis.
Andrew Reyes: The armamentarium in the treatment of AML and other leukemias was greatly enhanced with the advent of immunotherapeutic approaches which are able to provide alternatives to chemotherapy, especially in the case of chemotherapy-resistant leukemias. The article presented explores a novel form of immunotherapy known as double-negative-T-cell (DNT) immunotherapy which is shown to be effective against AML cell lines non-susceptible to other forms of immunotherapy such as CAR-T cell therapy and NK therapy. Furthermore, this article elucidates the molecular positive feedback loop between NKG2D, DNAM-1, and IFNγ which is thought to have a role in the leukemia-specific cytotoxicity of DNTs.
Morgan Yun: T-ALL, also known as T-Acute Lymphoblastic Leukemia, is a neoplastic monoclonal proliferation of abnormal immature T lymphocytes in bone marrow. It is known to have a high relapse rate. Using a multitude of techniques, cytogeneticists can examine cell activity to see the effects of different drugs. This is very useful in determining possible treatments. This paper focuses on the effects of Tetrandrine (TET), a potential anti-leukemic drug, on T-ALL development. Read more about TET and T-ALL in the following paper.
David Chung: This article explores the prognostic implications of additional copies of the Philadelphia chromosome and a loss of chromosome 9 upon cases of Acute Lymphoblastic Leukemia. The study shows that there is a poorer prognosis when these additional abnormalities arise, and it suggests that they should be taken into consideration for the future.
Anna Okabe: The purpose of this article is to define the main characteristics of pediatric T-ALL with t(11:14) and to analyze the prognosis. It compares the results of two treatment trials conducted by EORTC and follows the course of 20 patients.
Diane Zhao: This article explores the fascinating phenomenon of the relationship between Down syndrome and leukemia, as they are often presented at the same time. Specifically, children with acute myeloid leukemia (AML), particularly the acute megakaryocytic leukemia (AMKL) subtype, have very high cure rates. Read this article to find out more!
Grace Yang: This article explores the CALR gene mutational profile in myeloproliferative neoplasms (MPN) with a non-mutated JAK2 gene. This is particularly interesting because scientists have yet to establish biomarkers for Essential Thrombocythemia and Primary Myelofibrosis, two types of MPNs. By understanding commonalities in genetic mutations for these diseases, we can better understand not only how they manifest, but also find cures for them.
Diane Zhao: Primary myelofibrosis (PMF) is a myeloid malignancy characterized by progressive marrow fibrosis and extramedullary hematopoiesis. In this paper, we explore the fascinating role of cytogenetics in the PMF disease mechanism, as some abnormalities can lead to favorable outcomes while others can lead to very unfavorable outcomes. Read about the devastating prognosis of abnormality in chromosome 17 in this article.
Vincent Tse: This paper reveals great implications in using in vivo models such as the zebrafish, Danio rerio, to study pathways altered in cancer in addition to screening potential drug treatments to alleviate symptoms in patients. Through this approach, the paper's focus on leukemia cancers such as B- and T-ALL shows promise in uncovering new details on the pathogenesis of various leukemia and giving us the opportunity to try new medicine to improve patient prognoses.
Vincent Tse: The advent of new technologies such as next-generation sequencing (NGS) has allowed researchers studying the pathogenesis of T-ALL to pinpoint specific pathways and genes affected by the disease. NGS enables researchers to know which genes are more upregulated or downregulated, providing insight into target treatment plans. In this study, the authors found that the apoptosis pathway is dysregulated as a result of overactive mTOR signaling which comes from overexpression of miRNAs that silence genes encoding mTOR inhibitors and proteins regulating apoptosis.
Vincent Tse: T-ALL's pathogenesis is still very unexplored and is continuing to be the topic of many cancer research studies. This article provides an update on the current and new knowledge regarding the biology and treatments available fo T-ALL, highlighting the most recent findings over the past 5 years.
Vincent Tse: This interesting study shows the effects of certain risk factors, such as occupational exposure to etiologic agents, on an individual's likelihood to be diagnosed with chronic myelomonocytic leukemia (CMML). Focusing on benzene exposure, the authors present results that do not support an increased risk for developing CMML associated with historical exposures to benzene.
Vincent Tse: Molecular cytogenetic techniques such as FISH have proven instrumental in aiding the studies of cytogenetic diseases. Conventional cytogenetics alone is not sufficient to give diagnoses or serve as the only means to study the pathophysiology of genetic abnormalities. This publication demonstrates that coupling molecular and conventional cytogenetics is critical in the clinical setting to make proper diagnoses to ensure that patients afflicted with diseases are receiving the proper care and treatment they deserve.
Andrew Nguyen: Common cytogenetic techniques that come to mind are FISH and conventional cytogenetics, but many geneticists use technologies like flow cytometry to corroborate and confirm clinical data. As scientists its important to be knowledgeable about diverse solutions to problems and this article shows the strengths of one method to diagnose multiple hematological diseases in an cost effective and timely way. With lots of parameters and embedded statistics software, flow cytometry is a promising technique in genetics. This article shows one innovating way to apply its strengths in monocytic leukemia.
Andrew Nguyen: Cytogenetics is a relatively understudied field, but current and future studies are beginning to change this trend. As research continues, the scientific community continues to find use in cytogenetic techniques to corroborate molecular data at presentation for better prognostics. This ALL study is encouraging because I am doing my own research on T-ALL, and its cool to see other contributions in this area of cytogenetics.
Vincent Tse: An intriguing review that discusses the overall progress made by IVF practices and studies that utilize molecular cytogenetic methods to identify different blastocyst-stage embryos to improve IVF outcomes. Parsing out the prevalence of euploid, uniform aneuploidy, and mosaicism, studies have shown the transfer of embryos with aneuploid or mosaicism to be associated with “higher miscarriage and lower implantation rates” in comparison to embryos with populations of euploid cells. This review sheds insight on the continual importance of using molecular cytogenetic methods to screen and diagnose embryos during IVF development to ensure successful implantation and healthy pregnancies via IVF.
Dr. Tirado: This is a very interesting article, new genetic markers and drugs for T-PLL have been discovered. However, comprehensive in vivo and ex vivo studies need to be done in conjunction with other clinical testing.