Novel Approaches for Epigenetic Therapy for Relapsed Acute Lymphoblastic Leukemia
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.
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 - November 2020
Dr. Resar and her team of scientists discovered a key gene, called HMGA1, which functions as a key molecular “switch” that becomes “flipped on” when normal blood cells transform into aggressive leukemia cells in relapsed pediatric acute lymphoblastic leukemia (ALL). The HMGA1 gene is normally expressed during embryonic development in stem cells where it enables these cells to grow rapidly and generate diverse tissues. In mature tissues, HMGA1 is silenced except in blood stem cells where it helps to generate blood, and in other adult stem cells, where it replenishes tissues after injury or normal wear and tear. However, when HMGA1 becomes abnormally activated in blood cells, it allows these cells to expand, transform into leukemic cells, and evade therapy, which fosters relapse. In transgenic mouse models, Dr. Resar’s team found that HMGA1 causes aggressive ALL which closely resembles relapsed ALL in children. They also tested CRISPR technology in relapsed pediatric ALL cells and found that eliminating HMGA1 gene expression results in cell death in the leukemic blasts. Using this model and others, they have gone on to identify underlying pathways that are turned on by HMGA1 at relapse and could be blocked in therapy. In particular, they found that HMGA1 flips on gene networks that activate cell growth and stem cell properties, while turning off those that stimulate an immune attack on the abnormal leukemic cells. Using Next Generation Sequencing technology in pediatric ALL cells that were banked by the Children’s Oncology Group (COG), they discovered that the same HMGA1 networks are dysregulated at relapse in children. The Resar team went on to identify drugs to target these pathways using an in silico approach called Connectivity Mapping (developed at the Broad Institute at MIT). This strategy revealed that drugs targeting the epigenome can block relapse-specific pathways. The epigenome refers to the structural organization of our DNA that is independent of the actual DNA sequence or “blueprint”. This is an exciting area of cancer research because there are many drugs that can safely modulate the epigenome. Dr. Resar is now testing these epigenetic drugs with other agents used in childhood ALL with the goal of treating or preventing relapse. Her team plans to translate the most promising results to the clinics to cure children with relapsed ALL. This work is also important because HMGA1 is highly expressed in many aggressive childhood cancers, such as neuroblastoma, Burkitts lymphoma, osteosarcoma, and other tumors. Dr. Resar has published over 90 manuscripts and currently holds two patents.