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Mutated Splicing Factors in Blood Disease

Mutated Splicing Factors in Blood Disease—RNA splicing links segments of messenger RNA into a “complete” template for protein synthesis and is regulated by proteins called splicing factors. Splicing-factor mutations can cause the blood diseases myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how those mutations caused disease wasn’t known. In a study published online on April 22 in Nature Cell Biology, co-first author Gaurav Choudhary, Ph.D., co-corresponding author, Amit K. Verma, M.B.B.S., and their team showed that a splicing-factor mutation triggers formation of  the protein IRAK4-L (an active form of the protein IRAK4), which leads to MDS/AML. The researchers also found that IRAK4-L’s expression in MDS/AML is mediated by the mutated U2AF1 splicing factor. IRAK4-L inhibitors suppressed leukemic growth of AML cells—a strategy that worked even better when the cells had U2AF1 mutations, indicating that U2AF1 mutations make IRAK4-L more targetable.  IRAK4 inhibitors will soon be tested in MDS clinical trials. Dr. Verma is professor of medicine and of developmental and molecular biology at Einstein and attending physician in oncology at Montefiore Einstein Center for Cancer Care. The research was co-led by Daniel Starczynowski, Ph.D., of Cincinnati Children’s Hospital and Jacqueline Boultwood, Ph.D., of the University of Oxford.

Tuesday, May 28, 2019
 
Finding the Root Causes of Blood Cancers

Finding the Root Causes of Blood Cancers—The enzyme TET2 play a key role in causing blood cancers, but how it become activated wasn’t known. In a study published online on April 3 in Cancer Discovery, co-senior authors Amit K. Verma, M.B.B.S., and Amittha Wickrema, Ph.D., of the University of Chicago report that the enzyme kinase JAK2 activates TET2 through phosphorylation. The researchers also discovered that JAK2V617F, a JAK2 mutation seen in blood cancers, is associated with increased TET2 activity, increased hydroxymethylation (an epigenetic alteration commonly found in blood cancers) and the overexpression of oncogenic genes.  These findings indicate that the phosphorylation and consequent activation of TET2, mediated byJAK2V617F, leads to epigenetic and oncogenic changes that may underlie the development of blood cancers. Dr. Verma is professor of medicine and of developmental and molecular biology at Einstein and attending physician in oncology at Montefiore Einstein Center for Cancer Care.

Wednesday, May 01, 2019
 
Understanding Kidney Cancer Progression

Understanding Kidney Cancer Progression—Clear cell renal cell carcinoma (CCRCC) is the most common type of kidney cancer. In a study published online on January 31 in the Journal of Clinical Investigation, Niraj Shenoy, MD., M.S., Amit K. Verma, M.B.B.S., and colleagues describe a new prognostic biomarker for this type of cancer called 5-hydroxymethylcytosine (5hmC). As kidney cancer advances, tumor levels of 5hmc progressively decrease. The researchers found that loss of 5hmC occurs because an aberrant metabolic intermediate inhibits enzymes called TET (Ten-eleven Translocation). Furthermore, the presence of ascorbic acid (Vitamin C) prevents the aberrant intermediate from affecting TET and restores 5hmC levels. High-dose intravenous ascorbic acid inhibited kidney cancer growth in a mouse model and increased 5hmc within the tumors. These findings have led to an ongoing multicenter randomized phase 2 clinical trial of vitamin C as an adjunct to standard of care treatment for metastatic and unresectable CCRCC. Dr. Verma is professor of medicine and of developmental and molecular biology at Einstein and attending physician in oncology at Montefiore Einstein Center for Cancer Care. Dr. Shenoy is an assistant professor of medicine at Einstein and attending physician in oncology at Montefiore Einstein Center for Cancer Care.

Thursday, March 21, 2019
 
Looking at the Origins of Leukemia

Looking at the Origins of Leukemia—Myelodysplastic syndromes (MDS) are precancerous blood conditions that frequently progress to acute myeloid leukemia (AML). MDS and AML are both characterized by the presence of blast cells (defective blood-forming stem cells), with higher levels present in AML. Both conditions also originate from clones (i.e., single defective stem cells). In a study published online on December 3 in Nature Medicine, Amit K. Verma, M.B.B.S., and Ulrich Steidl M.D., Ph.D., examined how stem cells evolve into MDS and AML. Jiahao Chen, Ph.D., a researcher in Dr. Steidl’s laboratory, used single-cell sequencing to compare the MDS and AML stem cells of seven patients whose MDS had progressed to AML. The study revealed that stem cell subclones not detectable in MDS blasts became dominant upon progression to AML. These results suggest that the current bulk-cell approach to analyzing cancer-related stem cells may overlook pre-existing rare aberrant stem cells that drive disease progression and the transformation of MDS to AML. Dr. Verma is professor of medicine and of developmental and molecular biology at Einstein and attending physician in oncology at Montefiore Einstein Center for Cancer Care. Dr. Steidl is the Diane and Arthur B. Belfer Faculty Scholar in Cancer Research, director of the Stem Cell Isolation and Xenotransplantation Facility and a professor of cell biology and of medicine at Einstein and associate chair for translational research in oncology at Montefiore.

Monday, December 10, 2018
 
Targeting Blood Cancers

Targeting Blood Cancers—Myelodysplastic Syndrome (MDS) often progresses to acute myeloid leukemia (AML). Both conditions are triggered by mutations in hematopoietic stem cells (HSCs), which generate all of a person’s blood cells. Mutated HSCs have so far proven resistant to treatment efforts. But in a new study, published online on  September 25 in  the Journal of Clinical Investigation, Aditi Shastri, M.B.B.S., Britta Will, Ph.D., Amit Verma M.B.B.S., Ulrich Steidl, M.D., Ph.D., and colleagues describe a new therapeutic strategy that might work. Dr. Verma and Dr. Steidl’s team had previously found that overexpression of the gene that codes for the transcription factor STAT3 is associated with MDS/AML cases that have a poor prognosis. In the study, they tested the experimental STAT3 inhibitor AZD9150 on MDS/AML stem cells from patients and on MDS/AML mouse models and found that AZD9150 successfully suppressed both STAT3 production and HSC proliferation. These promising preclinical results suggest that AZD9150 may be an effective MDS/AML therapy. Dr. Shastri is an assistant professor of medicine at Einstein and an attending physician in oncology at Montefiore Einstein Center for Cancer Care. Dr. Verma is professor of medicine and of developmental and molecular biology at Einstein and attending physician in oncology at Montefiore Einstein Center for Cancer Care. Dr. Will is an assistant professor of medicine and of cell biology at Einstein. Dr. Steidl is the Diane and Arthur B. Belfer Faculty Scholar in Cancer Research, director of the Stem Cell Isolation and Xenotransplantation Facility and a professor of cell biology and of medicine at Einstein and associate chair for translational research in oncology at Montefiore.

Friday, December 07, 2018
 
Combatting Myelodysplastic Syndrome

Combatting Myelodysplastic Syndrome—In the bone marrow disorder Myelodysplastic Syndrome (MDS), hematopoietic (blood-forming) stem cells give rise to poorly formed or defective blood cells. The National Heart, Lung, and Blood Institute has awarded Amit K. Verma, M.B.B.S., and Ulrich G. Steidl, M.D., Ph.D., a five-year, $2.1 million grant to study the role played by the IL8/CXCR2 pathway in causing MDS and to see if  targeting that pathway can prevent the syndrome from developing.  The research could lead to new insights into treating MDS as well as blood cancers such as leukemia. Dr. Verma is a professor of medicine and of developmental and molecular biology at Einstein and attending physician in oncology at Montefiore Einstein Center for Cancer Care. Dr. Steidl is the Diane and Arthur B. Belfer Faculty Scholar in Cancer Research, director of the Stem Cell Isolation and Xenotransplantation Facility and a professor of cell biology and of medicine at Einstein and associate chair for translational research in oncology at Montefiore. (1R01HL139487)

Wednesday, November 28, 2018
 
New Mutations Found in Rare Lymphoma/Leukemias

New Mutations Found in Rare Lymphoma/Leukemias—Adult T-cell leukemia/lymphoma (ATLL) is a rare but lethal cancer involving CD4 T-cells. ATLL is diagnosed most often in Japan and in the Caribbean, where the prognosis is worse for reasons that have been unclear. In a study published online on August 13 in Blood, Murali Janakiram, M.D., Amit K. Verma, M.B.B.S., B. Hilda Ye, Ph.D., and colleagues sequenced the genomes of cells from 30 Caribbean-American ATLL patients. Compared to Japanese patients, the Caribbean-American ATLL patients had a distinct genomic profile and a significantly higher frequency of epigenetic mutations, which is associated with a worse prognosis. The findings support a clinical trial testing whether Caribbean-American ATLL patients can benefit from DNA methyltransferase (DNMT) inhibitors, which can “correct” epigenetic mutations. Dr. Janakiram is an assistant professor of medicine. Dr. Verma is professor of medicine and of developmental and molecular biology at Einstein and attending physician in oncology at Montefiore Einstein Center for Cancer Care. Dr. Ye is an associate professor of cell biology at Einstein.

Wednesday, October 03, 2018
 
New Therapeutic Target for Melanomas

New Therapeutic Target for Melanomas—The invasiveness of cancers can be influenced by methylation and demethylation, epigenetic processes that alter the gene activity of cells without changing the genetic code. In a new study published online on July 25 in JCI Insight, Orsolya Giricz, Ph.D., and Amit K. Verma, M.B.B.S., analyzed a group of melanomas in which demethylation was coupled with overexpression of the CSF-1 receptor (CSF-1R), a protein that influences the activity of immune cells. This combination increased the growth and invasiveness of cancerous cells, especially when mutations involving the BRAF gene were present. Inhibiting the enzyme that activates CSF-1R or decreasing of CSF-1R’s expression slowed the melanomas’ advance. The findings reveal a previously unknown role for CSF-1R and suggest that it may be a good target for future melanoma therapies. Dr. Verma is professor of medicine and of developmental and molecular biology at Einstein and attending physician in oncology at Montefiore Einstein Center for Cancer Care. Dr. Giricz is an associate in Dr. Verma’s lab at Einstein.

Thursday, September 06, 2018
 
Epigenetic Markers in Pancreatic Cancer

Epigenetic Markers in Pancreatic Cancer—Cancers sometimes start when external influences cause changes in DNA. These so-called epigenetic modifications can alter gene expression—silencing a gene or over-activating it, for example. In a study featured on the cover of the November issue of Genome Research, Amit Verma, M.B.B.S., reported that pancreatic cancers have unique epigenetic modifications in a regulatory portion of DNA known as Hydroxymethylcytosine (5-hmC). He and his team found that 5-hmC was abnormally distributed at locations in the genome that regulate the expression of several genes associated with cancer, such as the gene BRD4. Dr. Verma is professor of oncology and of developmental and molecular biology at Einstein and attending physician in oncology at Montefiore Einstein Center for Cancer Care. The study’s first author is Sanchari Bhattacharyya, Ph.D., a research associate in the department of medicine.

Friday, December 22, 2017
 
Investigating the Cause of Myelodysplastic Syndrome

Investigating the Cause of Myelodysplastic Syndrome—Within the bone marrow, hematopoietic stem cells (HSCs) occupy niches that include stromal and mesenchymal cells. In myelodysplastic syndromes (MDS), which precede acute myeloid leukemia, HSCs behave abnormally, either because of genetic aberrations or epigenetic alterations to DNA that influence whether genes are expressed or not. In a study published online on July 6 in Cancer Research, collaborators found that novel epigenetic alterations in the bone marrow microenvironment are critically important in causing MDS to progress. More specifically, the presence of an abnormally high number of methyl groups (hypermethylation) in stromal cells activated the Wnt/β-catenin signaling pathway in MDS stem cells, stimulating their progression to leukemia. The findings suggest that drugs that inhibit DNA methyltransferases (DNMTs) that are used to treat MDS can exert their beneficial actions via influencing the surrounding cells of the bone marrow. Senior author, Amit Verma, M.B.B.S., is professor of medicine and of developmental and molecular biology. First author Tushar Bhagat, Ph.D., is a postdoctoral fellow in Dr. Verma’s lab at Einstein.

Tuesday, September 26, 2017
 
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