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A distinct subpopulation of leukemia initiating cells in acute precursor B lymphoblastic leukemia: quiescent phenotype and unique transcriptomic profile

In leukemia, a distinct subpopulation of cancer-initiating cells called leukemia stem cells (LSCs) is believed to drive population expansion and tumor growth. Failing to eliminate LSCs may result in disease relapse regardless of the amount of non-LSCs destroyed. The first step in targeting and elimi...

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Autores principales: Lee, Alex Q., Konishi, Hiroaki, Duong, Connie, Yoshida, Sakiko, Davis, Ryan R., Van Dyke, Jonathan E., Ijiri, Masami, McLaughlin, Bridget, Kim, Kyoungmi, Li, Yueju, Beckett, Laurel, Nitin, Nitin, McPherson, John D., Tepper, Clifford G., Satake, Noriko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9533407/
https://www.ncbi.nlm.nih.gov/pubmed/36212452
http://dx.doi.org/10.3389/fonc.2022.972323
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author Lee, Alex Q.
Konishi, Hiroaki
Duong, Connie
Yoshida, Sakiko
Davis, Ryan R.
Van Dyke, Jonathan E.
Ijiri, Masami
McLaughlin, Bridget
Kim, Kyoungmi
Li, Yueju
Beckett, Laurel
Nitin, Nitin
McPherson, John D.
Tepper, Clifford G.
Satake, Noriko
author_facet Lee, Alex Q.
Konishi, Hiroaki
Duong, Connie
Yoshida, Sakiko
Davis, Ryan R.
Van Dyke, Jonathan E.
Ijiri, Masami
McLaughlin, Bridget
Kim, Kyoungmi
Li, Yueju
Beckett, Laurel
Nitin, Nitin
McPherson, John D.
Tepper, Clifford G.
Satake, Noriko
author_sort Lee, Alex Q.
collection PubMed
description In leukemia, a distinct subpopulation of cancer-initiating cells called leukemia stem cells (LSCs) is believed to drive population expansion and tumor growth. Failing to eliminate LSCs may result in disease relapse regardless of the amount of non-LSCs destroyed. The first step in targeting and eliminating LSCs is to identify and characterize them. Acute precursor B lymphoblastic leukemia (B-ALL) cells derived from patients were incubated with fluorescent glucose analog 2-(N-(7-Nitrobenz-2-oxa-1, 3-diazol-4-yl) Amino)-2-Deoxyglucose (NBDG) and sorted based on NBDG uptake. Cell subpopulations defined by glucose uptake were then serially transplanted into mice and evaluated for leukemia initiating capacity. Gene expression profiles of these cells were characterized using RNA-Sequencing (RNA-Seq). A distinct population of NBDG-low cells was identified in patient B-ALL samples. These cells are a small population (1.92% of the entire leukemia population), have lower HLA expression, and are smaller in size (4.0 to 7.0 μm) than the rest of the leukemia population. All mice transplanted with NBDG-low cells developed leukemia between 5 and 14 weeks, while those transplanted with NBDG-high cells did not develop leukemia (p ≤ 0.0001-0.002). Serial transplantation of the NBDG-low mouse model resulted in successful leukemia development. NBDG-medium (NBDG-med) populations also developed leukemia. Interestingly, comprehensive molecular characterization of NBDG-low and NBDG-med cells from patient-derived xenograft (PDX) models using RNA-Seq revealed a distinct profile of 2,162 differentially-expressed transcripts (DETs) (p<0.05) with 70.6% down-regulated in NBDG-low cells. Hierarchical clustering of DETs showed distinct segregation of NBDG-low from NBDG-med and NBDG-high groups with marked transcription expression alterations in the NBDG-low group consistent with cancer survival. In conclusion, A unique subpopulation of cells with low glucose uptake (NBDG-low) in B-ALL was discovered. These cells, despite their quiescence characteristics, once transplanted in mice, showed potent leukemia initiating capacity. Although NBDG-med cells also initiated leukemia, gene expression profiling revealed a distinct signature that clearly distinguishes NBDG-low cells from NBDG-med and the rest of the leukemia populations. These results suggest that NBDG-low cells may represent quiescent LSCs. These cells can be activated in the appropriate environment in vivo, showing leukemia initiating capacity. Our study provides insight into the biologic mechanisms of B-ALL initiation and survival.
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spelling pubmed-95334072022-10-06 A distinct subpopulation of leukemia initiating cells in acute precursor B lymphoblastic leukemia: quiescent phenotype and unique transcriptomic profile Lee, Alex Q. Konishi, Hiroaki Duong, Connie Yoshida, Sakiko Davis, Ryan R. Van Dyke, Jonathan E. Ijiri, Masami McLaughlin, Bridget Kim, Kyoungmi Li, Yueju Beckett, Laurel Nitin, Nitin McPherson, John D. Tepper, Clifford G. Satake, Noriko Front Oncol Oncology In leukemia, a distinct subpopulation of cancer-initiating cells called leukemia stem cells (LSCs) is believed to drive population expansion and tumor growth. Failing to eliminate LSCs may result in disease relapse regardless of the amount of non-LSCs destroyed. The first step in targeting and eliminating LSCs is to identify and characterize them. Acute precursor B lymphoblastic leukemia (B-ALL) cells derived from patients were incubated with fluorescent glucose analog 2-(N-(7-Nitrobenz-2-oxa-1, 3-diazol-4-yl) Amino)-2-Deoxyglucose (NBDG) and sorted based on NBDG uptake. Cell subpopulations defined by glucose uptake were then serially transplanted into mice and evaluated for leukemia initiating capacity. Gene expression profiles of these cells were characterized using RNA-Sequencing (RNA-Seq). A distinct population of NBDG-low cells was identified in patient B-ALL samples. These cells are a small population (1.92% of the entire leukemia population), have lower HLA expression, and are smaller in size (4.0 to 7.0 μm) than the rest of the leukemia population. All mice transplanted with NBDG-low cells developed leukemia between 5 and 14 weeks, while those transplanted with NBDG-high cells did not develop leukemia (p ≤ 0.0001-0.002). Serial transplantation of the NBDG-low mouse model resulted in successful leukemia development. NBDG-medium (NBDG-med) populations also developed leukemia. Interestingly, comprehensive molecular characterization of NBDG-low and NBDG-med cells from patient-derived xenograft (PDX) models using RNA-Seq revealed a distinct profile of 2,162 differentially-expressed transcripts (DETs) (p<0.05) with 70.6% down-regulated in NBDG-low cells. Hierarchical clustering of DETs showed distinct segregation of NBDG-low from NBDG-med and NBDG-high groups with marked transcription expression alterations in the NBDG-low group consistent with cancer survival. In conclusion, A unique subpopulation of cells with low glucose uptake (NBDG-low) in B-ALL was discovered. These cells, despite their quiescence characteristics, once transplanted in mice, showed potent leukemia initiating capacity. Although NBDG-med cells also initiated leukemia, gene expression profiling revealed a distinct signature that clearly distinguishes NBDG-low cells from NBDG-med and the rest of the leukemia populations. These results suggest that NBDG-low cells may represent quiescent LSCs. These cells can be activated in the appropriate environment in vivo, showing leukemia initiating capacity. Our study provides insight into the biologic mechanisms of B-ALL initiation and survival. Frontiers Media S.A. 2022-09-21 /pmc/articles/PMC9533407/ /pubmed/36212452 http://dx.doi.org/10.3389/fonc.2022.972323 Text en Copyright © 2022 Lee, Konishi, Duong, Yoshida, Davis, Van Dyke, Ijiri, McLaughlin, Kim, Li, Beckett, Nitin, McPherson, Tepper and Satake https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Lee, Alex Q.
Konishi, Hiroaki
Duong, Connie
Yoshida, Sakiko
Davis, Ryan R.
Van Dyke, Jonathan E.
Ijiri, Masami
McLaughlin, Bridget
Kim, Kyoungmi
Li, Yueju
Beckett, Laurel
Nitin, Nitin
McPherson, John D.
Tepper, Clifford G.
Satake, Noriko
A distinct subpopulation of leukemia initiating cells in acute precursor B lymphoblastic leukemia: quiescent phenotype and unique transcriptomic profile
title A distinct subpopulation of leukemia initiating cells in acute precursor B lymphoblastic leukemia: quiescent phenotype and unique transcriptomic profile
title_full A distinct subpopulation of leukemia initiating cells in acute precursor B lymphoblastic leukemia: quiescent phenotype and unique transcriptomic profile
title_fullStr A distinct subpopulation of leukemia initiating cells in acute precursor B lymphoblastic leukemia: quiescent phenotype and unique transcriptomic profile
title_full_unstemmed A distinct subpopulation of leukemia initiating cells in acute precursor B lymphoblastic leukemia: quiescent phenotype and unique transcriptomic profile
title_short A distinct subpopulation of leukemia initiating cells in acute precursor B lymphoblastic leukemia: quiescent phenotype and unique transcriptomic profile
title_sort distinct subpopulation of leukemia initiating cells in acute precursor b lymphoblastic leukemia: quiescent phenotype and unique transcriptomic profile
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9533407/
https://www.ncbi.nlm.nih.gov/pubmed/36212452
http://dx.doi.org/10.3389/fonc.2022.972323
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