Sowing Seeds of Discontent
Robert Lowsky, MD
Dr. Lowsky indicated no relevant conflicts of interest.
Walkley CR, Olsen GH, Dworkin S, et al. A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor gamma deficiency. Cell. 2007;129:1097-110.
Chronic myeloid disorders are a heterogeneous group of nonlymphoid hematopoietic neoplasms that can be divided into those which display (the myelodysplastic syndromes [MDSs]) or do not display (the myeloproliferative disorders [MPDs]) significant dysmyelopoiesis. MPDs typically exhibit terminal myeloid cell expansion in the blood and bone marrow (BM). The classic types include polycythemia vera, essential thrombocytosis, chronic myelogenous leukemia, and chronic idiopathic myelofibrosis. In these disorders, the neoplastic clone is considered intrinsic to the hematopoietic cell and originates in a multipotent progenitor cell, whereas the marrow microenvironment has long been thought a bystander and not a cause. In a recent article in Cell, Walkley and colleagues link alterations in the marrow microenvironment with the subsequent development of perturbed granulopoiesis resembling an MPD.
It was previously shown that the retinoic acid receptor (RAR) subtypes RARα and RARγ are widely expressed in immature and maturing hematopoietic cell types. To further determine the role of RARγ in the production of hematopoietic cells, Walkley and colleagues made mice deficient for RARγ and report that these mice developed significantly increased granulocytes and granulocyte/macrophage progenitors (GMPs) in the blood, BM, and spleen by eight weeks of age. The myeloproliferative phenotype was continued throughout the lifespan of the mice and became more pronounced with age. By 12 months of age the RARγ-/- mice developed splenomegaly, extramedullary hematopoiesis, and anemia with steadily progressive granulocytosis and thrombocytosis. Unexpectedly, this phenotype was due entirely to a deficiency of RARγ in the microenvironment and was not intrinsic to the hematopoietic cell; transplant studies revealed that BM from wild-type mice transplanted into RARγ-/- mice rapidly developed the myeloproliferative phenotype. In contrast, wild type recipients of RARγ-/- or RARγ+/+ BM had similar blood, marrow, and spleen cellularity during the six months of monitoring. Histologic sections of tibiae revealed significantly reduced trabecular bone in the RARγ-/- mice, yet this reduction in the osteoblastic marrow niche did not impair hematopoietic stem cell (HSC) self-renewal. Taken together, these data suggest that the RARγ-/- microenvironment increases the proliferation and production of the relatively mature hematopoietic cells but does not affect the numbers of the immature progenitor and HSCs.
Walkley and colleagues demonstrate that loss of one of the major receptors for vitamin A, RARγ, results in a marrow microenvironment that induces a myeloproliferative phenotype. Although the mice failed to develop leukemic transformation, this study raises the possibility of a tumorigenic niche and provides data supporting the idea that niche dysfunction may have a role in the development of hematopoietic malignancies. It is easy to speculate how this can occur: a tumorigenic niche can supply inappropriate levels of growth factors that promote hematopoietic cell proliferation or inhibit apoptosis. The loss of trabecular bone following RARγ deficiency may lead to HSC expansion and/or mobilization of these or other progenitor cells to the spleen and extramedullary sites that provide a more permissive environment to myeloid proliferation and differentiation due to the loss of inhibitory signals normally provided by the osteoblastic niche. This study does not negate the importance of acquired genetic change in the malignant transformation to leukemia. Rather, it adds a complementary concept and suggests that understanding the contributions of how the marrow microenvironment sows seeds of discontent in the MPDs and other hematologic malignancies is important in understanding the pathogenesis of these diseases.
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Are You Ready?
In April 2003, a silent killer quietly invaded Toronto just days before the annual meeting of the American Association for Cancer Research (AACR). Thousands were quarantined after six people died of severe acute respiratory syndrome (SARS) and the number of suspected cases spiked. The world watched as colleagues in Canada struggled to find a way to deal with this medical emergency and public health crisis that forced ACCR to cancel their meeting. While we do not know when the next crisis may hit, we do know that future natural or man-made emergencies are a certainty. Given this likelihood, are you prepared to care for your patients, your staff, and yourself when the next crisis hits? How does care change in the face of a crisis when you may be at risk? These are just some of the important issues hematologists must consider and lessons we must learn from past experiences around the world.
Emergency preparedness is the topic of this year's ASH-EHA Policy Forum. In partnership with the European Hematology Association (EHA), ASH will explore important strategic questions that force us to reflect on the role we need to be prepared to play as hematologists during public health crises. This year's session will take place immediately before the Plenary Scientific Session, on Sunday, December 9, from 12:30 to 1:30 p.m. in Hall A1. The session will be co-chaired by ASH President Dr. Andrew Schafer and EHA President Dr. Willem Fibbe. We are delighted that renowned experts Drs. Don Low and Albert Osterhaus have agreed to stimulate our thinking about this topic and allow us to learn from their personal experiences.
Dr. Low saw the SARS epidemic unfold from his vantage point as Microbiologist-in-Chief at the Toronto Medical Laboratories and Mount Sinai Hospital, a diagnostic laboratory serving 100 hospitals in the Greater Toronto area. He will share his unique perspective about the challenges his colleagues and staff faced and offer insights that hematologists will want to consider in his presentation titled "SARS Outbreak in Toronto: Lessons Learned."
Dr. Osterhaus, widely recognized as "The Virus Hunter" for his expertise and sometimes unconventional methods in studying infectious diseases, was trained as a veterinarian. He turned to virology after he recognized the significance and impact of viruses that cross the species barrier. He founded the Netherlands National Institute for Public Health and Environment and heads a 100-person lab at Erasumus MC in Rotterdam. At the height of the SARS epidemic, he headed the first laboratory to provide evidence demonstrating that the disease was caused by a coronavirus that usually resides in civet cats and other carnivorous animals.
There will be time for questions from the audience after the speakers have shared their remarks. Please mark your calendar for this special policy forum.
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