Split decision: Stem cell signal linked with cancer growth

Researchers at the University of California, San Diego School of Medicine have identified a protein critical to hematopoietic stem cell function and blood formation. The finding has potential as a new target for treating leukemia because cancer stem cells rely upon the same protein to regulate and sustain their growth.Hematopoietic stem cells give rise to all other blood cells. Writing in the February 2, 2014 advance online issue of Nature Genetics, principal investigator Tannishtha Reya, PhD, professor in the Department of Pharmacology, and colleagues found that a protein called Lis1 fundamentally regulates asymmetric division of hematopoietic stem cells, assuring that the stem cells correctly differentiate to provide an adequate, sustained supply of new blood cells.Asymmetric division occurs when a stem cell divides into two daughter cells of unequal inheritance: One daughter differentiates into a permanently specialized cell type while the other remains undifferentiated and capable of further divisions.”This process is very important for the proper generation of all the cells needed for the development and function of many normal tissues,” said Reya. When cells divide, Lis1 controls orientation of the mitotic spindle, an apparatus of subcellular fibers that segregates chromosomes during cell division.”During division, the spindle is attached to a particular point on the cell membrane, which also determines the axis along which the cell will divide,” Reya said. “Because proteins are not evenly distributed throughout the cell, the axis of division, in turn, determines the types and amounts of proteins that get distributed to each daughter cell. By analogy, imagine the difference between cutting Earth along the equator versus halving it longitudinally. In each case, the countries that wind up in the two halves are different.”When researchers deleted Lis1 from mouse hematopoietic stem cells, differentiation was radically altered. Asymmetric division increased and accelerated differentiation, resulting in an oversupply of specialized cells and an ever-diminishing reserve of undifferentiated stem cells, which eventually resulted in a bloodless mouse.”What we found was that a large part of the defect in blood formation was due to a failure of stem cells to expand,” said Reya. “Instead of undergoing symmetric divisions to generate two stem cell daughters, they predominantly underwent asymmetric division to generate more specialized cells. As a result, the mice were unable to generate enough stem cells to sustain blood cell production.”The scientists next looked at how cancer stem cells in mice behaved when the Lis1 signaling pathway was blocked, discovering that they too lost the ability to renew and propagate. …

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Tiny diamonds to boost treatment of chemoresistant leukemia

Sep. 11, 2013 — By binding multiple molecules of a common leukemia drug with nanodiamonds, scientists from the National University of Singapore (NUS) and University of California, Los Angeles (UCLA) managed to boost the delivery of the drug to leukemic cells and retain the drug within the cells to combat the cancer.This novel discovery, reported for the first time, addresses one of the major challenges in the treatment of leukemia where the cancer cells develop ways to pump drugs out of the body before they can do their job, particularly after they are exposed to chemotherapeutics.Developed by Dr Edward Chow, Principal Investigator at the Cancer Science Institute of Singapore and Assistant Professor at the Department of Pharmacology, Yong Loo Lin School of Medicine at NUS, in collaboration with Professor Dean Ho of the UCLA School of Dentistry, this innovation shows promise for greater efficacy in treating leukemia, particularly in non-adherent cells.The findings were first published online in the medical journal Nanomedicine: Nanotechnology, Biology, and Medicine.When leukemia becomes drug-resistantDaunorubicin is currently one of the most common drugs used to treat leukemia. The drug works by slowing down or stopping cancer cells from growing, causing many of them to die. It is also common, however, for leukemia to become resistant to this drug after treatment.One mechanism by which this opposition, commonly known as chemoresistance, happens is through the expression of drug transporter pumps in leukemia cells that actively pump out chemotherapeutics, including Daunorubicin.Innovative use of nanodiamondsCurrent approaches to neutralising chemoresistance have centred on developing competitive inhibitors. These efforts have limited success, with challenges like high toxicity levels and less-than-promising results during clinical trials.The team of scientists from NUS and UCLA turned to nanodiamonds, which are tiny, carbon-based particles that are 2 to 8 nanometers in diameter, as an option to address chemoresistance. Dr Chow studied the biological basis of how nanodiamonds can potentially overcome chemoresistance.The scientists bound the surfaces of nanodiamonds with Daunorubicin, and the hybrid nanodiamond-drug complexes were introduced to leukemic cells. The research team found that nanodiamonds could carry the drug to the cancer cells without being pumped out. Due to their non-invasive sizes and unique surface features, nanodiamonds can be easily released without blocking up blood vessels.Dr Chow said, “The use of nanodiamonds offers a promising combination of biocompatibility and the capability to enhance therapeutic efficacy. Furthermore, our initial safety tests both in vitro and in vivo indicate that they are well tolerated which is a promising step towards continued translational development.””Nanodiamonds are promising therapeutic vehicles, and one of our current goals is to determine which drugs would be optimally delivered by the nanodiamond towards specific disease models that would best benefit a patient in the future,” added Prof Ho, who is with the Division of Oral Biology and Medicine and is also Co-Director of the Jane and Jerry Weintraub Center for Reconstructive Biotechnology at the UCLA School of Dentistry. Dr Ho is also a Professor of Bioengineering at UCLA.Further ResearchThe team noted that further development and safety evaluation of nanodiamond systems are necessary to realise their full potential. …

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Genetic cause of childhood leukemia identified

Sep. 8, 2013 — For the first time, a genetic link specific to risk of childhood leukemia has been identified, according to a team of researchers from Memorial Sloan-Kettering Cancer Center, St. Jude Children’s Research Hospital, University of Washington, and other institutions. The discovery was reported online today in the journal Nature Genetics.”We’re in uncharted territory,” said study author Kenneth Offit, MD, MPH, Chief of the Clinical Genetics Service at Memorial Sloan-Kettering. “At the very least this discovery gives us a new window into inherited causes of childhood leukemia. More immediately, testing for this mutation may allow affected families to prevent leukemia in future generations.”The mutation was first observed in a family treated at Memorial Sloan-Kettering of which several family members of different generations had been diagnosed with childhood acute lymphoblastic leukemia (ALL). A second, non-related, leukemia-prone family cared for at a different hospital was later found to have the same mutation. A series of experiments were conducted confirming that the observed mutation compromised the normal function of the gene, which may increase the risk of developing ALL.The inherited genetic mutation is located in a gene called PAX5, which is known to play a role in the development of some B cell cancers, including ALL. PAX5, a transcription factor or “master gene,” regulates the activity of several other genes and is essential for maintaining the identity and function of B cells. In all study participants, one of the two copies of the PAX5 gene was missing, leaving only the mutated version. …

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Epigenetic factor likely plays a key role in fueling most common childhood cancer

June 10, 2013 — Changes in an epigenetic mechanism that turns expression of genes on and off may be as important as genetic alterations in causing pediatric acute lymphoblastic leukemia (ALL), according to a study led by scientists at St. Jude Children’s Research Hospital and published in the June 10 online edition of the Journal of Clinical Investigation.The results suggest the mechanism called cytosine methylation plays a previously under-appreciated role in the development of leukemia. Cytosine methylation involves adding or removing methyl groups to cytosine, which is a building block of DNA.The study is the most comprehensive effort yet to identify and understand genetic and epigenetic factors that work together to cause ALL, the most common childhood cancer. ALL is a cancer of white blood cells known as lymphocytes. Scientists at St. Jude and Weill Cornell Medical College collaborated on the project.Researchers used a variety of techniques to examine hundreds of thousands of methylation sites across the genome in normal and leukemic lymphocytes, including samples from more than 160 children with ALL. Investigators found that known ALL subgroups, which are defined by chromosomal alterations, have unique methylation profiles. Those profiles correlated with different patterns of gene expression.”It is well known that different leukemia subgroups have distinct patterns of gene expression that are important in the development of leukemia,” said Charles Mullighan, MBBS (Hons), MSc, M.D., an associate member of the St. Jude Department of Pathology. Mullighan and Ari Melnick, M.D., Gebroe Professor Hematology/Oncology at Weill Cornell Medical College, are the study’s co-corresponding authors.”We have assumed that the underlying genetic changes are important determinants of those gene expression profiles. …

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Normal molecular pathway affected in poor-prognosis childhood leukemia identified

June 6, 2013 — Through genetic engineering of laboratory models, researchers at Dartmouth-Hitchcock Norris Cotton Cancer Center have uncovered a vulnerability in the way cancer cells diverge from normal regenerating cells that may help treat children with leukemia as reported in the journal PNAS on June 3, 2013. Dartmouth researchers are trying to understand the key pathways that distinguish how a normal blood cell grows and divides compared to the altered growth that occurs in leukemia. In addition to the treatment of leukemia, the work has relevance for expanding umbilical cord blood or bone marrow stem cells for transplantation.Leukemia often occurs due to chromosomal translocations, which are broken chromosomes that cause blood cells to grow uncontrollably. One gene that is involved in chromosomal translocations found at high frequency in childhood leukemia is the MLL1 (Mixed Lineage Leukemia 1) gene. Conventional chemotherapy is very ineffective at curing patients with this translocation, in contrast to other types of childhood leukemia, which are relatively curable.Using genetic engineering, the researchers generated a mouse model to discover genes that are regulated by MLL1 in hematopoietic stem cells, the cells that give rise to all white and red blood cell types. In the course of these studies, they identified several unique properties of the normal MLL1 pathway in hematopoietic stem cells that may be exploited to better treat leukemia harboring MLL1 translocations.”We discovered that many genes that depend upon the normal MLL1 protein are involved in maintaining hematopoietic stem cells, thus manipulating this pathway could be a way to expand cells from normal bone marrow or umbilical cord blood donors to improve transplantation of these cell types, which is a procedure used to treat certain chemotherapy-resistant cancers,” said Patricia Ernst, PhD, co-director Cancer Mechanisms, Dartmouth-Hitchcock Norris Cotton Cancer Center, associate professor of Genetics and of Microbiology and Immunology at the Geisel School of Medicine at Dartmouth, Hanover, NH.As principle investigator, Ernst and her team set out to discover the genetic pathways controlled by the normal form of the MLL1 protein and leukemogenic MLL1 fusion proteins specifically in hematopoietic stem cells (HSCs). Delineation of these pathways will facilitate research by her group and others aimed at developing strategies to kill leukemia cells without harming HSCs, which are often profoundly affected by current chemotherapeutic regimens. In performing this research, they also discovered a new molecular pathway that controls normal HSC biology.”We demonstrate in this study, that some direct MLL1 target genes in HSCs are affected by Menin loss (a protein involved in the inherited disorder, Multiple Endocrine Neoplasia), and some are not,” said Ernst. “This is a fundamentally important observation that demonstrates this category of chromatin modifiers utilizes different protein complexes/mechanisms to target different classes of genes in different cell types.”Ernst points out that this highly desirable outcome that would not have been predicted for this targeted therapy and may illustrate that drugs blocking the interaction of these two proteins (currently under development by other groups) leave normal hematopoiesis intact. She is working on follow-up studies of this finding.Research funded by NIH HL090036 and RR16437 as well as additional grants from American Cancer Society, Gabrielle’s Angel Foundation for Cancer Research, Lady Tata Memorial Trust, and the Lauri Strauss Leukemia Foundation.

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Genetic testing of rare blood cancer reveals new mutation

June 5, 2013 — A recent article in the New England Journal of Medicine describes genetic testing of a rare blood cancer called atypical chronic neutrophilic leukemia (CNL) that revealed a new mutation present in most patients with the disease. The mutation also serves as an Achilles heel, allowing doctors at the University of Colorado Cancer Center to prescribe a never-before-used, targeted treatment. The first patient treated describes his best snowboarding season ever.”I’m a crazy sports fan,” says the patient. “I go 30 days a season. I may be the oldest guy snowboarding on the mountain, but I’m not the slowest!”When he lost a few pounds from what eventually proved to be undiagnosed cancer, the patient was initially pleased. “I was lighter and could snowboard better — ride better, jump better,” he says. Then he took a blood test and his white blood cell count was far in excess of the normal range. His doctor couldn’t find a cause and so they watched and waited. A couple months later, another blood test showed his white count was even higher.”That’s when I decided to go to the University of Colorado Hospital,” he says. There he met Daniel A. …

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