American Society of Hematology highlights St. Jude research, leadership

Gene therapy results for XSCID study announced at annual hematological meeting in Atlanta.

 

St. Jude Children's Research Hospital scientists present research at the 2017 American Society of Hematology (ASH) meeting, taking place in Atlanta from Dec. 9 to Dec. 12.

Select Onsite Experts

Data Analysis

Leukemia

Severe Combined Immunodeficiency Disease

Gene Therapy

Sickle Cell Disease


 

CEO and President James R. Downing, MD, Honored with 2017 E. Donnall Thomas Lecture and Prize

The E. Donnall Thomas Lecture and Prize recognizes discoveries and practice-changing research in the field of hematology. In August, ASH announced St. Jude CEO and President James R. Downing, MD, would be honored for his work in hematopathology and molecular biology of childhood leukemia.

Downing will present the lecture on “The Molecular Pathology of Pediatric Acute Leukemia,” at 9 a.m. ET on Monday, Dec. 11.

Read more at hematology.org.


 

Select Oral Abstracts

When: Saturday, Dec. 9, 7:45 a.m. ET
Location: Georgia World Congress Center, Building B, B405-407
Title: TP53 Germline Variations Influence the Predisposition and Prognosis of Acute Lymphoblastic Leukemia in Children
Abstract: 31

Inherited TP53 variations associated with high-risk ALL

Evidence recently shows about 1 percent of childhood acute lymphoblastic leukemia (ALL) cases may be related to inherited genetic variations in the TP53 tumor suppressor gene. The variations are also associated with a greater risk of poor treatment outcomes, including as much as a one-in-four chance of developing second cancers after therapy. Researchers sequenced TP53 in 3,858 children with ALL and identified 22 high-risk TP53 variants. Germline variations are carried in the DNA of every cell and are usually inherited. Children with the variants were more likely to be older at diagnosis and more likely to have the high-risk subtype hypodiploid ALL. The patients were also about three times less likely than those with normal TP53 to survive their disease. “The findings suggest that we need to be extra mindful of the therapy given to this group of patients to minimize their risk of treatment-related cancers,” said Jun J. Yang, PhD, an associate member of the St. Jude Departments of Pharmaceutical Sciences and Oncology. Maoxiang Qian, PhD, a postdoctoral fellow in Yang’s laboratory, will present the research.


 

When: Saturday, Dec. 9, 7:45 a.m. ET
Location: Georgia World Congress Center, Building B, B216-217
Title: RGL2 Deficiency Impairs Human Erythropoiesis by Altering Terminal Erythroid Differentiation and Apoptosis
Abstract: 8

RGL2 mutations tied to bone marrow failure syndrome

Harry Lesmana, MD, a St. Jude clinical hematology/oncology fellow, will outline evidence that inherited variations in the RGL2 gene are associated with a bone marrow failure syndrome. The association was discovered through whole exome sequencing of DNA from a toddler who had bone marrow failure with reduced platelets, red blood cells and white blood cells. The patient’s heart, liver and other organ systems were also affected. Researchers found RGL2 expression was 70 to 96 percent reduced in the patient’s white blood cells and in developing red blood cells. Working in human blood stem cells in the laboratory, Lesmana and his colleagues found that reduced RGL2 delayed red blood cell maturation. RGL2 is part of the Ras signaling pathway that regulates important cellular functions and is often disrupted in cancer. While RGL2 has not previously been linked to bone marrow failure or red blood cell production (erythropoiesis), the Ras pathway has been associated with erythropoiesis.


 

When: Saturday, Dec. 9, 6:30 p.m. ET
Location:
Georgia Aquarium, Pacific Room
Title:
Exploring the Relationship between Self-Management and Disease Knowledge Among Adolescents with Sickle Cell Disease
Abstract:
3350

Caregiver insights predict adolescent readiness for adult healthcare system

Are older teenagers with sickle cell disease prepared to make the transition from pediatric to adult care? St. Jude research suggests that health care providers looking for answers should ask the patients’ parents or other caregivers. “Our findings show caregivers are better evaluators of their adolescents’ readiness to make the transition than adolescents themselves,” said Anjelica Saulsberry, a medical student working with Jane Hankins, MD, an associate member of the St. Jude Department of Hematology. The transition can have serious consequences for individuals with sickle cell disease. Mortality rates for the disease increase sharply after age 18. Saulsberry will present research that involved 36 adolescents with sickle cell disease and their parents or other caregivers. Researchers found that caregivers’ perceptions about their teens’ disease knowledge and self-management skills early in adolescence helped predict their readiness to transition to adult care at age 18. “These finding highlight the insight caregivers have to offer about how we as health care providers can better prepare their children to successfully navigate the adult health care system and advocate for themselves,” Hankins said.


 

When: Sunday, Dec. 10, 8 a.m. ET
Location: Georgia World Congress Center, Building B, B213-214
Title:
Ulk1 Kinase Mediates Clearance of Free α-Globin in β-Thalassemia
Abstract: 285

Existing drug could eliminate excess alpha globin in beta thalassemia

A promising approach to treating the inherited blood disorder beta thalassemia focuses on using drugs to rescue red blood cells from the toxic buildup of hemoglobin components. Hemoglobin is the protein red blood cells use to carry oxygen. Normal hemoglobin has four protein chains—two alpha globin and two beta globin. Beta thalassemia patients have too little beta globin, which causes alpha globin to accumulate in excess. Without its normal beta globin partner, excessive alpha globin is toxic to red blood cells. Ultimately, excessive alpha globin kills red blood cells, resulting in anemia and other sometimes life-threatening symptoms associated with beta thalassemia. Researchers have identified an enzyme, Ulk1, which helps red blood cells eliminate excess alpha globin. Treatment of mice with an FDA-approved drug predicted to increase Ulk1 activity reduced alpha globin buildup and extended red blood cell lifespan. “This study identifies a novel possible approach to treat one of the most common blood disorders in the world,” said Mitchell Weiss, MD, PhD, chair of the St. Jude Department of Hematology. Christophe Lechauve, PhD, a staff scientist in the laboratory of Weiss will present the research. 


 

When: Sunday, Dec. 10, 4:30 p.m. ET
Location: Georgia World Congress Center, Building C, C101
Title: Interim Results from a Phase I/II Clinical Gene Therapy Study for Newly Diagnosed Infants with X-Linked Severe Combined Immunodeficiency Using a Safety-modified Lentiviral Vector and Targeted Reduced Exposure to Busulfan
Abstract: 523

St. Jude gene therapy shows early promise for infants with X-linked SCID

Ewelina Mamcarz, MD, assistant member of the St. Jude Department of Bone Marrow Transplantation and Cellular Therapy, will detail preliminary evidence that St. Jude gene therapy is safe and effective for infants with X-linked severe combined immunodeficiency (XSCID). An inherited mutation in a single gene meant the infants were born with little to no immune protection. The problem is sometimes called ‘bubble boy’ disease, a reference to the infection-control measures used to protect patients. The patients are the first XSCID infants to receive a lentivirus, or vector, which St. Jude researchers re-engineered and enhanced for safety. The vector ferries a correct copy of the mutant gene to the patients’ blood-forming stem cells. Patients also received low-dose chemotherapy with busulfan to help the gene-corrected cells survive and flourish. Brian Sorrentino, MD, of the St. Jude Department of Hematology, led the vector-development effort.

Read the Press Release >


 

When: Sunday, Dec. 10, 4:30 p.m. ET
Location: Georgia World Congress Center, Building B, B213-214
Title: Characterization of Causal Variants at the GATA3 Loci Associated with Susceptibility to Ph-like Acute Lymphoblastic Leukemia
Abstract: 475

GATA3 research could point to new strategies in treating Ph-like ALL

Hui Zhang, MD, PhD, will present research detailing how a germline variation in the GATA3 gene fuels development of a high-risk leukemia subtype. The subtype is Philadelphia chromosome-like ALL (Ph-like ALL). The findings lay the foundation for exploring strategies to improve survival of patients with the high-risk GATA3 variants, which are more common in Hispanic Americans and other people with Native American ancestry. The research included targeted sequencing of GATA3 in 5,008 pediatric ALL patients. Scientists showed the GATA3 variants switched on GATA3 gene expression. Overexpression of GATA3 led to increased expression of a leukemia oncogene, CRLF2. The findings suggest that overexpression of GATA3 sets the stage for rearrangement of CRLF2, which is the defining molecular feature in up to half of Ph-like ALL cases. Zhang previously worked in the laboratory of Jun J. Yang, PhD, an associate member of the St. Jude Departments of Pharmaceutical Sciences and Oncology. Zhang is now at Women and Children’s Medical Center, Guangzhou, China. 


 

When: Monday, Dec. 11, 5:15 p.m. ET
Location: Georgia World Congress Center, Building B, B308-309
Title: Effects of Hydroxyurea (HU) on Neurocognitive Performance in Children with Sickle Cell Disease: A Prospective Trial
Abstract: 760

Hydroxyurea protects against cognitive dysfunction in young sickle cell patients

Winfred Wang, MD, a member of the St. Jude Department of Hematology, will show evidence suggesting hydroxyurea protects and possibly improves cognitive functioning of school-aged children with sickle cell anemia. Researchers tracked changes in IQ scores and aspects of cognitive performance in 21 children and adolescents with sickle cell disease following one year of hydroxyurea treatment. Average patient IQ scores rose about 3 points, as did scores on other performance measures. In contrast, IQ scores tended to decline in 11 sickle cell patients whose parents opted against hydroxyurea therapy. The study is among the first to demonstrate cognitive benefit from hydroxyurea, which is proven to reduce pain crises and other symptoms of the inherited blood disorder. The patients were 7 to 18 years old. “This study provides another reason hydroxyurea should be offered to and taken by all patients with sickle cell anemia,” Wang said.


 

When: Monday, Dec. 11 at 7:15 a.m. ET
Location: Georgia World Congress Center, Building C, C202-C204
Title: CREBBP Histone Acetyltransferase Domain Mutations Result in Dexamethasone Resistance in B-Progenitor Acute Lymphoblastic Leukemia
Abstract: 560

A mutation yields clues for reversing drug-resistance in relapsed ALL 

Yunchao Chang, PhD, a St. Jude postdoctoral fellow in the lab of Charles Mullighan, MD, MBBS, will offer a potential strategy for restoring glucocorticoid sensitivity in children with relapsed acute lymphoblastic leukemia (ALL). The work builds on previous research from Mullighan’s lab and reports that CREBBP is the most commonly mutated gene identified to date in relapsed pediatric ALL. In this study, the gene was mutated in more than 21% of 174 patients with relapsed disease. The CREBBP protein is an epigenetic regulator of gene expression. Mutated, the protein is associated with glucocorticoid resistance. Glucocorticoids are a cornerstone of leukemia treatment. Working in mice and human cells growing in the lab, researchers detailed how CREBBP mutations cripple steroid functioning and disrupt normal CREBBP function. Investigators then screened thousands of drugs and other compounds and showed how one (GNE-049) restored steroid sensitivity in human cells with the mutation. “This offers a possible model for developing precision medicines to target the mutations driving relapsed leukemia,” said Mullighan, a member of the St. Jude Department of Pathology.