Recent advances in acute myeloid leukemia stem cell biology

Horton, Sarah J.; Huntly, Brian J. P.

doi:10.3324/haematol.2011.054734

Cited by 127 publications

(123 citation statements)

References 74 publications

(89 reference statements)

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“…7,10–12,40,46 We are not aware of any published reports indicating that they should differ from AML blasts in their intrinsic susceptibility to RDL by antibodies or antibody-derived agents in combination with NK cells. For most patients with CD34-positive AML, the relapse-relevant AML-LSCs are contained predominantly in the compartments of CD34-positive and (CD34-positive CD38-negative) cells.…”

Section: Resultsmentioning

confidence: 98%

“…1 2 Prognosis for patients with relapsed disease is generally poor, and therefore, new treatment options are urgently needed. Recurrence of the disease is thought to be caused by Leukemia Stem Cells (LSCs) and leukemic progenitor cells which survived CT. 3–7 New treatment strategies attempting to reach prolonged and deeper remissions therefore need to aim at an improved elimination of AML LSCs. Immuno-therapeutic approaches are promising for this purpose.…”

Section: Introductionmentioning

confidence: 99%

“…46 On aggregate, the published reports agree that CD123 is expressed with far greater frequency and surface densities on AML-LSCs and progenitor cells than on normal HSCs. 7 A fraction of normal HSCs may therefore survive therapies targeting CD123. 27 Finally, CD123 is also expressed on cells from other hematologic malignancies including Acute Lymphoblastic Leukemia (ALL), Chronic Myeloid Leukemia (CML), Myelo-Dysplastic Syndromes (MDS), Hodgkin Lymphoma (HL), Hairy Cell Leukemia (HCL) and others.…”

Section: Introductionmentioning

confidence: 99%

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Dual-targeting triplebody 33-16-123 (SPM-2) mediates effective redirected lysis of primary blasts from patients with a broad range of AML subtypes in combination with natural killer cells

et al. 2018

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A number of agents designed for immunotherapy of Acute Myeloid Leukemia (AML) are in preclinical and early clinical development. Most of them target a single antigen on the surface of AML cells. Here we describe the development and key biological properties of a tri-specific agent, the dual-targeting triplebody SPM-2, with binding sites for target antigens CD33 and CD123, and for CD16 to engage NK cells as cytolytic effectors. Primary blasts of nearly all AML patients carry at least one of these target antigens and the pair is particularly promising for the elimination of blasts and leukemia stem cells (LSCs) from a majority of AML patients by dual-targeting agents. The cytolytic activity of NK cells mediated by SPM-2 was analyzed in vitro for primary leukemic cells from 29 patients with a broad range of AML-subtypes. Blasts from all 29 patients, including patients with genomic alterations associated with an unfavorable genetic subtype, were lysed at nanomolar concentrations of SPM-2. Maximum susceptibility was observed for cells with a combined density of CD33 and CD123 above 10,000 copies/cell. Cell populations enriched for AML-LSCs (CD34pos and CD34pos CD38neg cells) from 2 AML patients carried an increased combined antigen density and were lysed at correspondingly lower concentrations of SPM-2 than unsorted blasts. These initial findings raise the expectation that SPM-2 may also be capable of eliminating AML-LSCs and thus of prolonging survival. In the future, patients with a broad range of AML subtypes may benefit from treatment with SPM-2.

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Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dual-targeting triplebody 33-16-123 (SPM-2) mediates effective redirected lysis of primary blasts from patients with a broad range of AML subtypes in combination with natural killer cells

et al. 2018

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“…In addition, more and more molecular lesions (aberrations), epigenetic changes and posttranslational modifications are acquired by CSC. As a result, CSC in an overt tumor is quite heterogeneous populations of cells, with varying combinations of molecular lesions and oncogenic pathways, resulting in a variable tumorigenic potential of CSC-subpopulations [31,[38][39][40][41][42][43]. Subclone formation is based on genomic instability and plasticity of CSC, patient-related factors (such as the immune system) and the increased rate of symmetrical cell divisions that lead to a continuous expansion and diversification of the CSC pool [38][39][40][41][42][43].…”

Section: Introduction and Historical Aspectsmentioning

confidence: 99%

“…As a result, CSC in an overt tumor is quite heterogeneous populations of cells, with varying combinations of molecular lesions and oncogenic pathways, resulting in a variable tumorigenic potential of CSC-subpopulations [31,[38][39][40][41][42][43]. Subclone formation is based on genomic instability and plasticity of CSC, patient-related factors (such as the immune system) and the increased rate of symmetrical cell divisions that lead to a continuous expansion and diversification of the CSC pool [38][39][40][41][42][43]. Subclone formation is also considered to contribute essentially to acquired resistance against diverse types of drugs (multidrug resistance) [38][39][40][41][42][43].…”

Section: Introduction and Historical Aspectsmentioning

confidence: 99%

The Vienna Cancer Stem Cell Club (VCSCC): First 10 Years and Future Perspectives

2013

JLS

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Abstract:In 2002, the Vienna Cancer Stem Cell Club (VCSCC) was inaugurated by a group of scientists at the Medical University of Vienna, with the primary goal to initiate and promote cancer stem cell (CSC) research in Austria and to exploit knowledge from this new discipline in translational approaches. During the first years following inauguration, the VCSCC-community was small and left without major funding. However, over time the consortium was able to launch several major project-lines, supported in part by the National Science Funds, a Genome Program, and the Ludwig-Boltzmann Society. Today, the VCSCC provides a robust intellectual platform for ongoing research in the field of translational oncology and CSC-research in Austria. In addition, the VCSCC is connected to several major CSC-networks and centers in Europe and in North America, and is a well-recognized group in the field. The VCSCC also organized a series of CSC Meetings and Conferences, and contributed essentially to a recently published classification of CSC. There is also hope that the VCSCC-consortium will further advance the field of CSC research in the future, and will create novel concepts, with the ultimate aim to improve anti-cancer therapy through elimination, suppression, or long-term control of cancer-initiating cells.

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Slow‐replicating leukemia cells represent a leukemia stem cell population with high cell‐surface CD74 expression

Li,

Cao,

Liu

et al. 2024

Molecular Oncology

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Persistence of quiescent leukemia stem cells (LSCs) after treatment most likely contributes to chemotherapy resistance and poor prognosis of leukemia patients. Identification of this quiescent cell population would facilitate eradicating LSCs. Here, using a cell‐tracing PKH26 (PKH) dye that can be equally distributed to daughter cells following cell division in vivo, we identify a label‐retaining slow‐cycling leukemia cell population from AML1‐ETO9a (AE9a) leukemic mice. We find that, compared with cells not maintaining PKH‐staining, a higher proportion of PKH‐retaining cells are in G0 phase, and PKH‐retaining cells exhibit increased colony formation ability and leukemia initiation potential. In addition, PKH‐retaining cells possess high chemo‐resistance and are more likely to be localized to the endosteal bone marrow region. Based on the transcriptional signature, HLA class II histocompatibility antigen gamma chain (Cd74) is highly expressed in PKH‐retaining leukemia cells. Furthermore, cell surface CD74 was identified to be highly expressed in LSCs of AE9a mice and CD34+ human leukemia cells. Compared to Lin−CD74− leukemia cells, Lin−CD74+ leukemia cells of AE9a mice exhibit higher stemness properties. Collectively, our findings reveal that the identified slow‐cycling leukemia cell population represents an LSC population, and CD74+ leukemia cells possess stemness properties, suggesting that CD74 is a candidate LSC surface marker.

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Recent advances in acute myeloid leukemia stem cell biology

Cited by 127 publications

References 74 publications

Dual-targeting triplebody 33-16-123 (SPM-2) mediates effective redirected lysis of primary blasts from patients with a broad range of AML subtypes in combination with natural killer cells

Dual-targeting triplebody 33-16-123 (SPM-2) mediates effective redirected lysis of primary blasts from patients with a broad range of AML subtypes in combination with natural killer cells

The Vienna Cancer Stem Cell Club (VCSCC): First 10 Years and Future Perspectives

Slow‐replicating leukemia cells represent a leukemia stem cell population with high cell‐surface CD74 expression

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