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The latest advances in the study of blood diseases presented at annual meeting of ASH

The 2016 American Society of Hematology Annual Meeting highlights research from St. Jude Children’s Research Hospital scientists and clinicians

Memphis, Tennessee, December 2, 2016

ASH Highlights

Charles Mullighan, MD, Accepts William Dameshek Prize for Contributions in ALL Research

Charles Mullighan

When: Tuesday, Dec. 6, 2016 at 9:30 a.m. PST
: Hall AB (San Diego Convention Center)
Title: Announcement of Awards: William Dameshek Prize, Henry M. Stratton Medal

Charles Mullighan, MD, MBBS, a member in the St. Jude Department of Pathology, will be awarded the 2016 William Dameshek Prize. The award recognizes Mullighan’s internationally acclaimed research on the pathogenesis and biology of acute lymphoblastic leukemia (ALL). Mullighan is a world leader in ALL research. In collaboration with James R. Downing, MD, St. Jude president and chief executive officer, Mullighan has led much of the scientific discovery work on the genomic basis of ALL. Mullighan now oversees research looking to develop targeted therapeutic strategies for genetically defined subsets of ALL, many with poor prognoses, in children and adults. His studies have had profound implications for the understanding of the genetic basis of ALL and have led to multiple new diagnostic and therapeutic approaches. The William Dameshek Prize, named for a past president of ASH and the original editor of the scientific journal Blood, recognizes recent outstanding contributions to the field of hematology by an investigator under age 50.


Research Identifies New Leukemia Predisposition Gene, Suggests Role in Disease Development and Treatment

Michelle Churchman, PhD

When: Tuesday, Dec. 6, 2016 at 7:30 a.m. PST
: Hall AB (San Diego Convention Center)
Title: Late-Breaking Abstracts Program: Germline Genetic Variation in IKZF1 and Predisposition to Childhood Acute Lymphoblastic Leukemia

Michelle Churchman, PhD, scientific manager of the Mullighan laboratory, will report on inherited variants of the IKZF1 gene that leave individuals at an increased risk for pediatric ALL. The work was a collaboration with the study’s co-corresponding author, Jun J. Yang, PhD, an associate member of the St. Jude Hematological Malignancies Program and Department of Pharmaceutical Sciences. IKZF1 joins several other genes that are associated with an inherited predisposition to develop ALL early in life. This study began with a genetic analysis of a single family with multiple cases of childhood ALL. Researchers identified mutations in IKZF1 that likely contribute to the disease. Sequencing of germline DNA from normal blood samples of more than 5,000 children with ALL identified 28 unique IKZF1 variants in 44 cases. Laboratory tests showed most of the variants disrupted the normal function of IKZF1, and in some cases, decreased sensitivity to chemotherapy drugs. Alterations in IKZF1 have been associated with high-risk forms of ALL that respond poorly to treatment.


Select Onsite Experts

Friday Scientific Workshop on Inherited Hematopoietic Malignancies


Education Program: Genetic Susceptibility to Leukemias
Introduction to Cancer Genetic Susceptibility Syndromes


Education Program: Pediatric Hematologic Malignancies 
Non-Hodgkin Lymphoma Across the Pediatric, Adolescent, and Young Adult Age Spectrum


Special-Interest Sessions
Gene Editing – Not just CRISPR


Select Oral Abstracts

Saturday, Dec. 3

When: Saturday, Dec. 3 at 8 a.m. PST
Location: San Diego Ballroom AB
Title: Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Genomic Discoveries in Myeloid Leukemogenesis
Abstract: 39

Ilaria Iacobucci, PhD, a postdoctoral fellow in the St. Jude Department of Pathology, will present evidence that a rare subtype of acute myeloid leukemia (AML) called acute erythroid leukemia (AEL) includes multiple genetic subtypes with distinct genomic features and clinical outcomes. About one-third of patients with the AEL subtype had specific mutations that suggest targeted therapies with tyrosine kinase/Ras inhibitors might be beneficial. The study is the first comprehensive genomic analysis of this rare form of AML in children and adults. Researchers used genome, exome and transcriptome sequencing to map the genomic landscape of 159 cases of AEL in patients from the U.S., Europe, Asia and Australia, and used this information to generate new experimental models of the disease. Iacobucci works in the Mullighan laboratory.

When: Saturday, Dec. 3 at 3 p.m. PST
Location: San Diego Ballroom AB
Title: Acute Lymphoblastic Leukemia: Therapy, excluding Transplantation: Clinical Results of Non-Immunotherapy Trials

Chengcheng Liu, PhD, a St. Jude postdoctoral fellow, will present evidence that underscores how variations in the ways patients respond to the drug asparaginase may decrease tolerance to mercaptopurine, an important drug in the treatment of pediatric ALL. Asparaginase and mercaptopurine are used together for successful ALL treatment, but doses of both drugs sometimes have to be limited due to drug toxicities. Such changes to therapy may jeopardize treatments. In this study, researchers found that patients who have lower antibody responses to asparaginase could not tolerate higher doses of mercaptopurine. “Mercaptopurine now joins a growing list of anti-leukemic drugs, including steroids and methotrexate, that interact with asparaginase and affect how patients tolerate chemotherapy,” said senior author Mary Relling, PharmD, chair of the St. Jude Department of Pharmaceutical Sciences. Liu works in Relling’s laboratory. The study involved 390 ALL patients treated on the St. Jude Total XV protocol. Patients with higher levels of asparaginase antibodies had higher tolerance for mercaptopurine. This observation could help guide future treatments by tailoring doses of both drugs to the specific responses of individual patients. Liu received an ASH Abstract Achievement Award for this work.

Sunday, Dec. 4

When: Sunday, Dec. 4 at 7:45 a.m. PST
Location: Marriott Grand 11-13
Title: Genetic Modeling and Therapeutic Targeting of ETV6-NTRK3 with Loxo-101 in Acute Lymphoblastic Leukemia
Abstract: 278

Kathryn Roberts, PhD, a staff scientist in the Mullighan laboratory, will report that the experimental targeted therapy LOXO-101 is remarkably effective in a mouse model of a high-risk subtype of ALL known as Philadelphia chromosome-like (Ph-like) ALL. LOXO-101 is designed to selectively inhibit a family of signaling proteins encoded by NTRK genes that promote cancer growth. LOXO-101 is currently in clinical trials for treatment of solid tumors with fusion genes involving NTRK genes. For this study, researchers created the first genetically engineered mouse model of Ph-like ALL with the ETV6-NTRK3 fusion gene. Treatment with LOXO-101 alone completely suppressed proliferation of leukemic cells in the preclinical model. The findings indicate that all newly identified ALL patients should be screened for the ETV6-NTRK3 fusion. Clinical trials are also warranted to test the effectiveness of LOXO-101 in combination with chemotherapy regimens.

When: Sunday, Dec. 4 at 5:15 p.m. PST
Location: Marriott Grand 11-13
Title: Genomic Landscape of Pediatric Mixed Phenotype Acute Leukemia
Abstract: 454

Thomas Alexander, MD, MPH, a physician scientist working in the Mullighan laboratory, will report on the genetic basis of a high-risk subtype of leukemia called mixed phenotype acute leukemia (MPAL). The results describe the first comprehensive genomic analysis of MPAL using 119 confirmed pediatric cases collected from 13 collaborative groups worldwide. The findings show that a subtype known as B/myeloid MPAL is characterized by frequent chromosomal rearrangements involving the ZNF384 gene. The T/myeloid subtype is characterized by mutations similar to early T-cell precursor ALL. In each subtype, the different phenotypes within a case of MPAL share a common genetic basis. These results will aid in efforts to design treatment strategies for MPAL.

Monday, Dec. 5

When: Monday, Dec. 5 at 8 a.m. PST
Location: Ballroom 20D
Title: Endothelial Cell-Expressed α Hemoglobin and Its Molecular Chaperone Ahsp Modulate Arterial Vascular Reactivity
Abstract: 557

Christophe Lechauve, PhD, staff scientist in the St. Jude Department of Hematology, will detail how the alpha subunit of the hemoglobin protein and a chaperone protein work together to fine-tune blood pressure. Lechauve works in the laboratory of Mitchell Weiss, MD, PhD, chair of the St. Jude Department of Hematology. Previous work reported on the role of the alpha hemoglobin subunit’s role in stimulating small blood-vessel constriction. Now investigators have identified how the chaperone protein alpha hemoglobin stabilizing protein (AHSP) contributes to the process. In red blood cell precursors, AHSP transiently binds and stabilizes alpha globin to facilitate assembly of the oxygen transporter hemoglobin A. In this study, researchers found that AHSP played a similar stabilizing role for alpha hemoglobin subunits expressed in endothelial cells lining the blood vessels. Specifically, in endothelial cells, AHSP stabilizes alpha hemoglobin prior to its interaction with endothelial nitric oxide synthetase. That sets the stage for degradation of nitric oxide, which stimulates vasoconstriction. Additional research is needed to understand how this process may contribute to human disease, including alpha thalassemia or high blood pressure.

When: Monday, Dec. 5 at 11:30 a.m. PST
Location: Room 33
Title: Hemophagocytic Lymphohistiocytosis (HLH) in Langerhans Cell Histiocytosis (LCH): A Multicenter Retrospective Descriptional Study
Abstract: 707

Deepak Chellapandian, MD, MBBS, a clinical fellow in the St. Jude Department of Bone Marrow Transplantation and Cellular Therapy, will report the results of a multi-center, international study that found it is not uncommon for two rare immune proliferative disorders to strike the same patient. The combination was associated with reduced survival. The disorders—Langerhans cell histiocytosis (LCH) and hemophagocytic lymphohistiocytosis (HLH)—are characterized by an abnormal buildup of immune cells in different organs. This study included 384 children and young adults with LCH that affected several organs. Researchers reported that 11 percent or 44 patients also had HLH. Five-year survival for patients with both disorders was 70 to 75 percent, compared to 98 percent for patients with multi-system LCH alone. More research is needed to improve diagnosis and treatment of HLH in patients with multisystem LCH. The senior author is Kim Nichols, MD, of the St. Jude Department of Oncology.

When: Monday, Dec. 5 at 5:30 p.m. PST
Location: Marriott Grand 11-13
Title: Comprehensive Functional Characterization of Germline ETV6 Variants Associated with Inherited Predisposition to Acute Lymphoblastic Leukemia in Children
Abstract: 1085

Rina Nishii, a student in the St. Jude Department of Pharmaceutical Sciences, will present evidence that germline mutations in the ETV6 gene contribute to leukemia by disrupting its role as a repressor of transcription during blood development. Nishii works in the laboratory of Jun J. Yang, PhD, an associate member of the St. Jude Hematological Malignancies Program and Department of Pharmaceutical Sciences. Previous research from Yang and others has linked inherited variations in ETV6 to an increased risk of developing ALL or other blood cancers. Until now, however, how the mutations changed gene function was largely unknown. This study provides an answer. Researchers evaluated 30 ETV6 variants from pediatric ALL patients and found 18 that resulted in the dramatic loss of function of the ETV6 protein. ETV6 mutations predispose individuals to develop ALL, but the alterations are not sufficient to cause the disease. In this study, whole genome sequencing of five ALL patients from two families with germline ETV6 variations identified other mutations that likely cooperate with ETV6 defects to trigger leukemia.