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Novel Approaches for Epigenetic Therapy for Relapsed Acute Lymphoblastic Leukemia

Institution: 
The Johns Hopkins University School of Medicine
Researcher(s): 
Linda Resar, MD & Andrei Thomas-Tikhonenko, PhD
Grant Type: 
Innovation Grants
Year Awarded: 
2017
Type of Childhood Cancer: 
Acute Lymphoblastic Leukemia (ALL)
Project Description: 

Background
Acute lymphoblastic leukemia (ALL) is the most common form of childhood leukemia and the leading cause of death in children with cancer. While therapy is often curative, ~15% of children will relapse with recurrent disease and abysmal outcomes. Why some children develop resistant disease remains unclear. 

Project Goal
To address this question, we are studying genetic pathways that cause relapse with the goal of designing therapies to treat children with relapsed disease. Our focus is the HMGA1 gene, which is up-regulated in childhood ALL with the highest levels at relapse. HMGA1 transforms normal blood cells into leukemia cells and causes aggressive leukemia in mice, recapitulating salient features of childhood ALL. This gene encodes a protein that acts as a “molecular switch” that “opens” DNA to turn on genes that are required by stem cells for rapid cell growth and development. Based on these exciting findings, we hypothesize that: 1) HMGA1 drives relapse in ALL by ‘flipping on” stem cell genes, and 2) targeting these pathways will put a “break” on abnormal growth and destroy stem-like leukemic blasts at relapse where HMGA1 expression is highest. To test this, we propose specific aims to 1) define the stem cell pathways up-regulated by HMGA1 at relapse and 2) screen for novel therapies that disrupt the aberrant pathways induced by HMGA1. This work will elucidate the abnormal DNA landscape imposed by HMGA1 in relapsed ALL and begin to identify new therapies for children with relapsed ALL.

Update - June 2020

Our ALSF project focuses on acute lymphoblastic leukemia (ALL), the most common form of childhood leukemia and the leading cause of death in children with cancer. While therapy is often curative, ~15% of children will relapse with recurrent disease and abysmal outcomes. Why some children relapse remains unclear. To address this question, we are studying genetic pathways that cause relapse with the goal of designing therapies to treat children with relapsed disease. Our focus is the HMGA1 gene, which is up-regulated in childhood ALL with the highest levels at relapse. This gene encodes a protein that acts as a “molecular switch” to “flip on” genes required by leukemic blasts to evade therapy and expand. By comparing leukemic blasts from children with relapse to those from children with long-term remissions, we discovered that the HMGA1 gene “signature” is flipped on at relapse. We also found that blocking HMGA1 in mouse models of relapsed ALL improves outcomes. We are now looking for drugs to target the HMGA1 relapse-specific signature. In a preliminary in silico drug screen, we discovered epigenetic drugs that block leukemic blast growth. Further studies are underway to test whether these drugs are active in mouse models of relapsed ALL. We plan to translate the most promising results to the clinics to treat children at risk for relapse. 

 

 
Co-funded by: 
Cure4Cam Childhood Cancer Foundation