American Society of Hematology

Scientific Spotlight Sessions

The following information is preliminary and subject to change.

The Scientific Spotlight Sessions are intended to provide an in-depth review on specific scientific topics. This year, speakers will discuss fundamental and translational insights into various hematologic disease mechanisms and their implications on disease onset and progression.

Each 90-minute session will be presented once in a small-venue format on either Sunday or Monday and will include ample time for audience questions and participation. These sessions are restricted to medical and research professionals only; no businesspersons or media will be admitted.

Scientific Spotlight Session at the ASH Annual Meeting

Biochemical and Genetic Insights Into MLL/11q23 Translocation Leukemia

Prior to molecular cloning of the gene disrupted at chromosome 11q23, it was clear that this chromosome translocation conferred unique biological characteristics on the corresponding leukemia, including the young age of patients at presentation and overall poor prognosis. Since molecular cloning of the genes affected at the 11q23 locus, the lessons learned from studying the MLL1 or KMT2A gene and its oncogenic variants have served as a paradigm for understanding epigenetic deregulation of gene expression in normal physiology and cancer. These studies dovetailed with a wealth of existing genetic data from studying homologous pathways in model organisms. Detailed biochemical, genetic, and molecular characterization of MLL1/KMT2A expression pathways have yielded far more important insights into chromatin-based gene regulation and targeting such gene pathways in cancer than originally anticipated. Despite important insights gained, molecularly-targeted therapeutics for patients with MLL1 translocations are now just becoming available, with multiple independent therapeutic strategies currently being pursued. This session will highlight genetic and biochemical insights impacting leukemogenesis. 

Dr. Scott Armstrong will discuss the actions of MLL fusion oncogenes and how they achieve deregulated gene expression programs on the path to leukemia. Understanding how genes are deregulated by MLL-fusion oncoproteins has led to discoveries converging on a multitude of associated chromatin modifying complexes. These insights have prompted the development of small molecular inhibitors that are being tested clinically and that may have relevance beyond MLL1-rearranged leukemias. Dr. Armstrong will discuss preclinical data assessing these novel therapeutic opportunities in the context of ongoing clinical development.

Dr. Ali Shilatifard will present biochemical and genetic studies demonstrating how epigenetic regulators and transcription elongation factors are altered from normal development to cancer, including hematologic malignancies. He will also discuss the use inhibitors against the activities of the epigenetic regulators and elongation factors for leukemic therapy.

Chair:

Patricia Ernst, PhD
University of Colorado
Denver, CO

Speakers:

Scott A. Armstrong, MD, PhD
Dana-Farber Cancer Institute
Boston, MA
Targeting Chromatin Complexes in MLL Rearranged Leukemia

Ali Shilatifard, PhD
Northwestern University
Chicago, IL
Regulation of MLL Stability

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Leukemia Predisposition Syndromes

Although hereditary factors were originally believed to account for only a small proportion of pediatric and adult cancers, recent studies incorporating germline genomic sequencing have revealed that an increasing number of patients develop the disease due to an underlying predisposition. The identification of an underlying predisposition is of significant clinical relevance, as this information guides cancer treatment and informs the need for cancer surveillance and risk-reducing measures. Furthermore, germline information enables genetic testing among family members and provides critical data on recurrence risk. This session will address the latest advances in the field as they relate to the evaluation and management of children and adults at increased genetic risk for cancer, including leukemia.

Dr. Kim Nichols will discuss the approaches being used for germline genetic testing and how these approaches are improving the understanding of inherited predisposition to cancer. She will review the sequencing of rare cancer prone kindreds, non-biased sequencing of large cohorts of cancer patients, and paired tumor-normal sequencing. Through these studies, several novel cancer-predisposing genes and/or genetic variants have been uncovered. As more patients are sequenced, more novel genotype-phenotype correlations will be made that will help elucidate the impact of germline mutations on presentation and outcome of the disease.

Dr. Hamish Scott will discuss leukemia and predisposition with a focus on the ongoing discovery of novel genes and germline sequence variants that increase the risk for both lymphoid and myeloid malignancies. He will discuss the complexities of germline variant interpretation and the clinical implications resulting from the identification of such genes and variants, including considerations for clinical care, such as molecular monitoring of clonal evolution and selection of family stem cell donors. Dr. Scott will discuss the reasons why predisposition to hematologic malignancies may be overlooked, the biological pathways involved, and the therapeutic implications.

Chair:

Kim E. Nichols, M.D.
St. Jude Children's Research Hospital
Memphis, TN

Speakers:

Kim E. Nichols, M.D.
St. Jude Children's Research Hospital
Memphis, TN
Identifying Novel Genetic Causes of Childhood Cancer

Hamish S. Scott, PhD
University of Adelaide
Adelaide, Australia
Novel Pathways to Leukemia Predisposition

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Myeloproliferative Neoplasms (MPN) Roundtable: How Will We Cure Myelofibrosis?

Among the negative myeloproliferative neoplasms (MPNs), myelofibrosis, both in its primary form and as a result of transformation from one of the other MPNs, has remained the most enigmatic and most challenging form of MPN to manage clinically. Allogeneic stem cell transplantation remains the only potentially curative treatment. This is likely due to the extraordinary complexity of the pathobiology of myelofibrosis. Among the most significant factors directing the development and progression of myelofibrosis are phenotypic driver and additional somatic mutations of the malignant MPN clone, their sequence of acquisition and interactions, the role of epigenetic modifications, and the bidirectional interactions between the malignant MPN clones and their microenvironment. Most important in the latter is the cause-and-effect role of inflammation. The in this session will discuss how these factors might initiate and cause progression of myelofibrosis and how this information can guide the rational management of this disease.

Dr. Ross Levine will review current insights into the molecular basis of MPN, including the role of genetic and epigenetic alterations in MPN initiation and progression. JAK-STAT signaling has a critical role in the malignant transformation of MPN hematopoietic stem cells, and mutations in epigenetic modifiers may exert important cooperative actions on MPN development and progression. Dr. Levine will discuss the development of clinically tractable genomic assays and new targeted therapeutic strategies, including combined inhibition of JAK and the epigenetic regulator isocitrate dehydrogenase.

Dr. Angela Fleischman will discuss the central role of inflammation in MPN. Excessive inflammation not only causes many of the debilitating symptoms associated with the disease but also drives the selective expansion of the MPN neoplastic clone. Inflammation may also be directly responsible for some pathologic features of the disease, notably bone marrow fibrosis. Dr. Fleischman will discuss the mechanisms of increased inflammatory cytokine production in MPN, as well as the effects of inflammation on both normal and neoplastic hematopoietic stem and progenitor cells. She will also propose a model whereby inflammatory insult upon a vulnerable hematopoietic stem cell pool drives the emergence of the MPN neoplastic clone.

Dr. Claire Harrison will discuss current therapeutic strategies in myelofibrosis. The development of JAK inhibitors is changing the focus of treatment of myelofibrosis, delivering tangible benefit to patients but not yet a cure. Progress in treatment options will require more accurate prognostic scores to better select patients, including their timing, for transplantation. Current focus is on treatment options that might include more specific inhibitors or a combination with a second agent to allow more optimal dosing of a JAK inhibitor or an added therapy to improve benefit. The challenge in assessing the benefits of novel therapies is the lack of robust surrogate markers for treatment success. This will be an important target for future translational research in MPN.

Chair:

Andrew I. Schafer, MD
Weill Cornell Medicine
New York, NY

Speakers:

Ross L. Levine, MD
Memorial Sloan Kettering Cancer Center
New York, NY
Basic and Translational Insights Into the MPNs

Angela Fleischman, MD, PhD
University of California Irvine
Irvine, CA
Inflammation in the MPNs

Claire N. Harrison, DM
Guy's and St. Thomas' Hospital
London, United Kingdom
Treatment Strategies in Myelofibrosis

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New Insights Into Neonatal Hematology: Not Just a Small Adult

Neonatal hematology is a relatively young field. While it has been long recognized that fetuses and neonates are physiologically distinct from older children and adults, there has been a limited understanding so far of how their distinct biological features impact the presentation or the management of neonatal hematological problems. This session will focus on improving understanding of fetal/neonatal physiology to provide insights into the presentation of inherited bone marrow failure syndromes (IBMFS) and into the frequently unrecognized consequences of anemia in neonates.

Dr. Peter Kurre will discuss how fetal development shapes the unique pathophysiology of hematopoietic failure in IBMFS. IBMFS represent a heterogeneous group of multisystem disorders that typically present with cytopenia in early childhood. Reflecting the role of many of the involved genes in core cellular functions and the diverse non-hematologic abnormalities seen in patients at birth, Dr. Kurre will summarize studies that have begun to explore the manifestations of IBMFS during fetal development.

Dr. Michael Georgieff will discuss the importance of the timing of anemia and the developmental stage-specific risks it poses to the neonate. Anemia, which may be frequently tolerated in this population because of a lack of overt signs, has a profound effect on neonatal organ development because it compromises the delivery of critical nutrients, including oxygen and iron, to rapidly developing organs with high metabolic rates. The brain is particularly vulnerable to these effects because its metabolic demand constitutes 60 percent of the neonate’s total energy need. Recent studies have shed light on the specific effects of anemia and its treatments on brain development as a function of the timing of anemia relative to critical periods of regional brain development. As such Dr. Georgieff will also discuss brain systems (i.e., hippocampus [learning and memory], myelin [speed of processing] and the cerebellum) that are at risk in neonates with anemia.

Chair:

Martha Sola-Visner, MD
Boston Children's Hospital
Boston, MA

Speakers:

Peter Kurre, MD
Oregon Health & Science University
Portland, OR
How Development Shapes the Pathophysiology of Inherited Bone Marrow Failure

Michael Georgieff, MD
University of Minnesota
Minneapolis, MN
Developmental-Stage Specific Consequences of Anemia in Neonates

Other Scientific Sessions

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