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Persistence of self-renewing leukemia cell progenitors during remission in children with B-precursor acute
Z Estrov1, M V Ouspenskaia, E A Felix
1Division of Medicine, University of Texas MD Anderson Cancer Center, Houston 77030.
Insights
Researchers identified persistent leukemia cells in children with acute lymphoblastic leukemia (ALL) using a novel method. These cells, capable of self-renewal, may explain disease relapse and inform future therapies.
Area of Science:
- Pediatric Oncology
- Molecular Biology
- Hematology
Background:
- A significant percentage of children with acute lymphoblastic leukemia (ALL) experience relapse, often due to persistent, undetectable leukemia cells.
- Effective therapies for relapsed ALL remain limited, highlighting the need to understand the mechanisms of treatment failure.
Purpose of the Study:
- To develop and evaluate a method for identifying residual leukemia cells in children with B-precursor ALL during remission.
- To investigate the characteristics and persistence of these residual leukemia cells.
Main Methods:
- Combined an ALL blast colony assay (BCA) with polymerase chain reaction (PCR) to isolate and analyze residual leukemia cells.
- Collected and analyzed sequential bone marrow aspirate specimens from eight patients with B-precursor ALL.
Main Results:
- Identified colony-forming leukemia cells with self-renewal capabilities that persisted for up to 15 months post-diagnosis in all patients.
- Confirmed the leukemic origin of these cells by sequencing their VHDJH DNA, matching the sequences found at diagnosis.
- Observed no relapses in patients during the early treatment phase, aligning with the typical late recurrence pattern in B-precursor ALL.
Conclusions:
- Persistent leukemia cells with self-renewal capacity are detectable in children with B-precursor ALL during early remission.
- These residual cells may represent leukemia progenitor cells and play a role in disease sustainment and eventual relapse.
- Further study of these persistent cells could elucidate mechanisms of ALL relapse and guide the development of novel therapeutic strategies.
Abstract:
No effective therapy is available for the majority of the 30-40% of children with acute lymphoblastic leukemia (ALL) who relapse. Since the morphologically undetectable, or occult, leukemia cells that persist during remission originate from the clone present at diagnosis, may also have both the capability to sustain the disease and to give rise to relapse, we are evaluating a method of identifying them. We have combined, for the first time, an ALL blast colony assay (BCA) and the polymerase chain reaction (PCR) to isolate residual leukemia cells in remission bone marrow aspirate specimens from eight patients with B-precursor ALL during early continuation therapy. We found colony-forming leukemia cells with in vitro self-renewal capability that survived chemotherapy for 15 months after diagnosis in all sequential specimens from these patients. To verify the leukemic nature of these cells their DNA was amplified by PCR and the product directly sequenced. In every case, the VHDJH sequence observed at diagnosis was found. None of the patients relapsed during this early phase of their treatment, consistent with the observation that patients with B-precursor ALL experience recurrence late in their course. Since it is possible that some of these persistent leukemia cells belong to the leukemia progenitor cell population that sustains the disease, the study of them could provide the means to determine the mechanisms of relapse.