Highlights of the 45th ASH Meeting

By Peter D. Emanuel, M.D.

Outstanding lectures from truly notable individuals. That is the best-fit description for many of the keynote lectures delivered at the December 6-9 meeting of the American Society of Hematology. Amongst the almost 19,000 registered global attendees, gigantic poster sessions, rooms filled to capacity for oral presentations, and burgeoning corporate and media involvement, it is comforting to see that there remain steadfast constants of the ASH meeting. These are the consistently brilliant scientific presentations delivered in the Ham-Wasserman Lecture, the E. Donnall Thomas Lecture, and the Presidential Symposium, as well as the important health issues brought to the fore in the Plenary Policy Forum.

The Ham-Wasserman Lecture was presented by Dr. Zhen-Yi Wang from Shanghai, China. His lecture was entitled “Treatment of Acute Leukemia by Inducing Differentiation and Apoptosis.” Dr. Wang used the illustrative history and success of acute promyelocytic leukemia (APL) as a model of differentiation therapy in acute leukemia. He re-traced the history of APL differentiation therapy back to its beginnings: all-trans retinoic acid (ATRA) therapy was first attempted in 1986, with the first report appearing in 1988. From those observations we rapidly catapult to present day when we can obtain a 90-95% complete remission rate in APL using a combination of ATRA and anthracycline-based chemotherapy. In clinical APL trials we are now exploring the combination of ATRA, with its differentiation-inducing abilities, with arsenic trioxide (ATO) and its potent apoptotic (and partial differentiation) inducing abilities. In addition, Dr. Wang's group is exploring in vitro addition of other compounds such as 8-CPT-cAMP to aid arsenic in its differentiation process. They are also utilizing microarrays to sort out the complex gene pattern in APL, and Dr. Zhang has isolated 509 altered genes in APL, 318 of which are upregulated, and 191 downregulated. Moving beyond APL, Dr. Wang's group is investigating the potential efficacy of SIH10 to induce growth inhibition and degrade the AML1-ETO oncoprotein in the Kasumi-1 cell line, which is derived from a human M2B leukemia with a t(8:21) translocation. Dr. Wang clearly believes that the penultimate therapy for all leukemias will include a combination of chemotherapy, differentiation-inducers, and apoptosis-inducers.

Dr. Ernest Beutler of The Scripps Research Institute, La Jolla, CA, delivered the 2003 E. Donnall Thomas Lecture entitled “Gaucher Disease: Multiple Lessons from a Single Gene Disease.” As always, Dr. Beutler began with several very illustrative patient presentations and noted the differences between type I (adult non-neuronopathic, indolent), type II (aggressive, acute infantile), and type III (intermediate juvenile) forms. He clearly delineated the pathway of sequential degradation of glucocerebroside, with different enzyme deficiencies in the pathway resulting in different diseases, including Tay-Sachs, Fabry, and Gaucher. Dr. Beutler theorized as to why Gaucher disease was so prevalent amongst the Ashkenazi Jewish population, with an incidence of 1:850 births. He doesn't believe it to be a random event of genetic drift because several different mutations are found, and the incidence of other lipid storage diseases is also increased in this population. But if Gaucher disease is not an accidental event, then it must be due to some selective advantage, the answer to which remains elusive. Dr. Beutler firmly believes that Gaucher disease illustrates the differences between a balanced polymorphism (in the Jewish population) and sporadic mutations. He convincingly conveyed the importance to understand the genotype/phenotype relationships and natural history, in order to best know how to treat this and other diseases. His take home lessons were: (1) don't perform a marrow exam or liver biopsy to diagnose Gaucher disease – the proper diagnostic test is the leukocyte beta-glucosidase assay, (2) if you believe in evidence-based medicine, then you should not administer >30 units/kg/month of enzyme replacement therapy for Gaucher, and enzyme should be administered at least once/week, and (3) genotype is only a rough guide to the phenotype in Gaucher disease, and we must investigate modifying genes, as well as environmental factors and epigenetic factors to explain why patients with identical genotypes differ in clinical disease manifestations. This last point applies not only to Gaucher, but to all “single gene” diseases.

The Presidential Symposium was on “Epigenetics in Hematology.” President Ron Hoffman assembled a group of three fascinating speakers, Dr. Arthur Beaudet from Baylor, Dr. Stephen Baylin from Johns Hopkins, and Dr. Gary Felsenfeld from the NIH. Together they delivered an integrative glimpse at how the field of epigenetics is emerging in hematology as well as other disciplines. Epigenetics is defined as “on top of” genetics, meaning that there is another layer of stable or semi-stable gene regulation on top of the primary nucleotide sequence. Dr. Beaudet discussed genomic imprinting and diseases, including the erasure and resetting of genomic imprinting, as well as the stochastic effect of grandparental origin and recombination. Genomic imprinting is an epigenetic phenomenon wherein maternal or paternal alleles are silenced but with only a few genes being involved in the process. For example, if there is a paternal deficiency on chromosome 15q11-q13 the result is Prader-Willi syndrome, whereas a maternal deficiency in the same chromosomal location results in Angelman syndrome. Dr. Baylin discussed epigenetic gene silencing and the paradigm that cancer was a disease of chromatin alterations. In cancer the most common change in the methylation pattern on genes is demethylation of a promoter which should be normally methylated. An alternative is hypermethylation of CpG islands, which is an epigenetic event affecting chromatin alterations. Many epigenetic gene silencing events may serve as permissive substrates for tumor progression steps to build upon, or these silencing events may even provide a gatekeeper type function. Dr. Felsenfeld delivered a primer on chromatin structure and the two problem areas within the genome wherein condensed and active chromatin can potentially interact, or adjacent gene systems may interact. He discussed the role of insulators as DNA sequence elements that block inappropriate interactions in the nucleus. There are two types of insulators: (1) those that have a barrier function and protect against silencing, and (2) those that enhance blocking function to protect against influence from outside enhancers.

This year's Plenary Policy Forum focused on possible approaches to comprehensive health insurance coverage in the U.S. Moderated by Ken Zuckerman, M.D., Chair of the ASH Government Affairs Committee, the session also featured two rousing speakers, Eric Book, M.D., and the Honorable John A. Kitzhaber, M.D. Dr. Zuckerman introduced the issues surrounding universal health care by relaying several important facts, including that more than 43 million people in the U.S. currently have no health insurance and that 75 million people are without health insurance for some portion of each year. In addition, he added that the majority of those without health insurance are employed. Dr. Eric Book, Senior Vice President for Health Services and Chief Medical Officer of Blue Shield of California, discussed Blue Shield's proposal to provide essential health coverage to all of California's 6.6 million uninsured residents — at a shared cost of $7.8 billion — and how the plan might be expanded to the entire country, with a $75 billion increase in federal health care spending. Former Oregon Governor Dr. John Kitzhaber passionately discussed why the U.S. needs to implement a universal health care system. He described his state's Medicaid “rationing” system — which he led through the legislature as Senate President, then implemented as Governor—that prioritized 700 different medical actions and procedures and guaranteed Medicaid recipients full coverage for the highest priority procedures. Finally, he concluded that meetings like the one ASH convened are critical to educate physicians about the different universal coverage options that are available and bring about reform.

If you missed any of these important lectures, they can easily be viewed at www.medsessions.com/ASH2003/.

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ASH Scholar Finds Way to Dramatically Increase Hematopoietic Stem Cells

Researchers from the Center for Regenerative Medicine and Techology (CRMT) and the Endocrine Unit at Massachusetts General Hospital (MGH) have found a novel way to significantly increase the production of hematopoietic stem cells in a mouse model. The study, published in the Oct. 23 issue of Nature, also identifies a potential treatment strategy that could duplicate this effect in patients, and the researchers are preparing clinical trials of that approach.

ASH Scholar Gregor Adams, Ph.D., of CRMT, Partners AIDS Research Center, and the MGH Cancer Center is one of the co-first authors of this study. “I believe that the success of our study published in Nature was due to our ability to examine the basic biology of the hematopoietic stem cell niche and then to extend this knowledge to a clinically relevant model of bone marrow transplantation,” said Dr. Adams. “We feel that this is a proof of the concept that augmenting the effectiveness of stem cell therapies can be achieved by targeting the stem cell microenvironment, rather than the stem cell directly.”

Clinical use of hematopoietic stem cells has always been difficult because they naturally occur in very small numbers and rarely reproduce. In recent years, many research groups have sought ways to expand stem cell populations, often by adding growth factors to bone marrow samples. The MGH researchers took a different approach by focusing on the natural environment in which stem cells develop, the marrow cavity inside long bones.

Because stem cells are usually found in the outer layer of marrow, the researchers felt that osteoblasts might also have an impact on stem cells. To investigate that possibility, the researchers first studied a group of transgenic mice with an overly active version of a protein that turns on osteoblasts. They found that, in addition to having excessive numbers of osteoblasts in their bones, the mice also had increased levels of stem cells in their bone marrow, although the amount of other marrow cells was normal. Further testing confirmed that this activated protein, a receptor for the bone-building parathyroid hormone (PTH), could be acting through a cellular-signalling pathway called Notch that is known to increase stem cell proliferation.

Following those findings, the researchers investigated whether injections of PTH might produce the same stem cell effect as seen in the transgenic mice. They first injected a group of normal mice with the hormone, and found similarly increased levels of stem cells in the bone marrow after four weeks' treatment. They then conducted bone marrow transplants on mice that had been irradiated to destroy their marrow, and found that marrow from mice treated with PTH was more effective in replacing recipient marrow than was tissue from normal mice.

To simulate the situation facing many patients needing stem cell transplants, the research team carried out a bone marrow transplant protocol including marrow destruction and the transfer of only a few stem cells on mice that had previously received PTH injections and on a control group. Where only 27 percent of the control mice survived for 28 days after transplantation, all of the PTH-treated mice survived, and examination of their marrow confirmed that the donor tissue had proliferated.

“The ASH Fellow Scholar Award program has played a major role in this work,” said Dr. Adams. “Not only did it provide the necessary support for my salary to be able to perform this research, but, through its support, to attend the ASH annual meeting. The meeting and the ASH Scholar Awards poster sessions allowed me to interact with experts in the field of stem cell biology and gain insight from their questions. I am very proud to be a recipient of the ASH Fellow Scholar Award and hope that it and the work it has enabled will assist my transition to an independent scientist in the field of hematologic research.”

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Attention Fellows and Junior Faculty

The 2004 ASH Scholar Award competition is just around the corner. This year's eligibility requirements and other important information are available on the ASH Web site.

The ASH Scholar Awards program is a highly competitive grants program that provides partial salary or other support during the critical period required for completion of training and achievement of status as an independent investigator. The goal of the program is to encourage beginning researchers to pursue a career specifically in hematology. The junior faculty award provides recipients with $75,000 per year for a two-year period and the fellow award provides $50,000 per year for a two-year period.

Please keep in mind that a required letter of intent is due on May 1, 2004. The applicant's curriculam vitae, brief abstract, and project title must be included with this letter. If you have any questions, please contact Karin Lombardi, ASH Development Manager.

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Call for Award Nominations

ASH members are invited to submit nominations for the William Dameshek Prize, Henry M. Stratton Medal, and E. Donnall Thomas Lecture and Prize for the year 2004. Letters of nomination must include a brief paragraph summarizing the nominee's contributions to hematology as well as a current bio-sketch or curriculum vitae. Please send nominations to: American Society of Hematology, Attn: LaFaundra Neville, 1900 M Street, NW, Suite 200, Washington, DC 20036, Fax: (202) 776-0545, E-mail: lneville@hematology.org.

WILLIAM DAMESHEK PRIZE
This award was named for the late Dr. William Dameshek, a past President of the Society. Dr. Dameshek made major contributions to the Society and was the first editor of its journal, Blood. The Dameshek Prize is awarded to an individual who has made an outstanding contribution in hematology during the preceding years. The Society's Awards Committee recommends the William Dameshek Prize recipient to the Executive Committee.

HENRY M. STRATTON MEDAL
In 1992 this award was changed from the Henry M. Stratton Lecture to the Henry M. Stratton Medal. The prize is named after the late Henry Maurice Stratton who made significant contributions to the Society and founded the medical publishing house of Grune & Stratton with Mr. L.H. Grunebaum. The Henry M. Stratton Medal honors an individual whose contributions to hematology are well recognized and have taken place over a period of several years. The Society's Awards Committee recommends the Henry M. Stratton Medal recipient to the Executive Committee.

E. DONNALL THOMAS LECTURE AND PRIZE
The lectureship was created in 1992 and named after the Nobel Prize laureate and past Society President E. Donnall Thomas, M.D. The E. Donnall Thomas Lecture and Prize recognizes pioneering research achievements in hematology. The Society's Awards Committee recommends the E. Donnall Thomas Lecture and Prize recipient to the Executive Committee.

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Annual Meeting Research Covered by Top Media Outlets

The scientific studies presented at the ASH annual meeting continue to garner attention from many of the nation's top media outlets, including the San Diego Union-Tribune, the Los Angeles Times, Reuters, and Bloomberg. More than 140 members of the press were present at the annual meeting in San Diego, and many positive news stories have originated from the meeting thus far. Media coverage of the meeting is expected to continue for the next few months. In total, is it estimated that more than 500 million people will read, see, or hear a news story that is based on a study presented at the 2003 meeting.

The Committee on Communications will continue to foster relationships with the media to ensure an accurate and positive perception of hematology by the press and the public.

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Call for Nominations for ASH Officers and Committee Membership

We need your help to identify “new blood”! The Society seeks a balanced committee membership that mixes bright, enthusiastic people with seasoned committee members. Since ASH is a volunteer association, we encourage and welcome any ASH member's self-nomination for committee service. A self-nomination is a good indication that you are keenly interested in helping to lead our Society into the future.

ASH is currently accepting nominations for leadership and committee member positions for the year 2005. Nominations received for committee membership are compiled and reviewed by the Nominating Committee in early May. Based on this pool of nominees, the Nominating Committee makes its recommendations to the President-Elect, who then makes the final appointments to the ASH standing and scientific committees in consultation with committee chairs in early October.

Nominations for any of the positions available must include name, institution, and a brief paragraph to describe why the ASH member is being recommended for service. These nominations should be sent to LaFaundra Neville. Nominations must include all requested information. Please visit the 2005 Call for Nominations Web page for more information about ASH Committees.

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American Society of Hematology New Members – As of December 2003

Active: 122

International: 59

TOTAL: 181

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