Revisiting <scp>CLEC</scp>12A as leukaemic stem cell marker in <scp>AML</scp>: highlighting the necessity of precision diagnostics in patients eligible for targeted therapy

Bill, Marie; Aggerholm, Anni; Kjeldsen, Eigil; Roug, Anne Stidsholt; Hokland, Peter; Nederby, Line

doi:10.1111/bjh.15711

Cited by 10 publications

(10 citation statements)

References 62 publications

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“…The combinations of DNMT3A with other mutations such as NRAS and KIT next to IDH1/2 mutations indicate a malignant phenotype 41‐44 . The finding of (pre‐) leukemic mutations in the CD34 + CLL‐1 ‐ fraction is consistent with a study reported by Bill and colleagues where pre‐leukemic mutations could be found in their long‐term colony initiating cell assay of CD34 + ALDH br CLL‐1 − cells 45 with targeted NGS.…”

Section: Discussionsupporting

confidence: 88%

Bimodal expression of potential drug target CLL‐1 (CLEC12A) on CD34+ blasts of AML patients

Ngai

Connie²,

Maguire³

et al. 2021

European J of Haematology

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Objectives This study aims to retrospectively assess C‐lectin‐like molecule 1 (CLL‐1) bimodal expression on CD34+ blasts in acute myeloid leukemia (AML) patients (total N = 306) and explore potential CLL‐1 bimodal associations with leukemia and patient‐specific characteristics. Methods Flow cytometry assays were performed to assess the deeper immunophenotyping of CLL‐1 bimodality. Cytogenetic analysis was performed to characterize the gene mutation on CLL‐1‐negative subpopulation of CLL‐1 bimodal AML samples. Results The frequency of a bimodal pattern of CLL‐1 expression of CD34+ blasts ranged from 8% to 65% in the different cohorts. Bimodal CLL‐1 expression was most prevalent in patients with MDS‐related AML (P = .011), ELN adverse risk (P = .002), NPM1 wild type (WT, P = .049), FLT3 WT (P = .035), and relatively low percentages of leukemia‐associated immunophenotypes (P = .006). Additional immunophenotyping analysis revealed the CLL‐1− subpopulation may consist of pre‐B cells, immature myeloblasts, and hematopoietic stem cells. Furthermore, (pre)‐leukemic mutations were detected in both CLL‐1+ and CLL‐1− subfractions of bimodal samples (N = 3). Conclusions C‐lectin‐like molecule 1 bimodality occurs in about 25% of AML patients and the CLL‐1− cell population still contains malignant cells, hence it may potentially limit the effectiveness of CLL‐1‐targeted therapies and warrant further investigation.

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Section: Discussionsupporting

confidence: 88%

Bimodal expression of potential drug target CLL‐1 (CLEC12A) on CD34+ blasts of AML patients

Ngai

Connie²,

Maguire³

et al. 2021

European J of Haematology

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“…The C-type lectin-like molecule-1 (CLL-1) is a promising alternative to the “classical” LSC targets ( 414 ). The majority of AML patients shows CLL-1 + LSCs, a marker not being expressed on HSCs ( 370 , 414 – 416 ). Compared to CD33, CLL-1 was not only more frequently and stronger expressed on LSCs, but also not or more weakly expressed on normal tissues leading to reduced off-target effects after treatment with a respective antibody-drug conjugate.…”

Section: Cscs and Their Origin At Tumor Initiationmentioning

confidence: 99%

Cancer Stem Cells—Origins and Biomarkers: Perspectives for Targeted Personalized Therapies

et al. 2020

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The use of biomarkers in diagnosis, therapy and prognosis has gained increasing interest over the last decades. In particular, the analysis of biomarkers in cancer patients within the pre- and post-therapeutic period is required to identify several types of cells, which carry a risk for a disease progression and subsequent post-therapeutic relapse. Cancer stem cells (CSCs) are a subpopulation of tumor cells that can drive tumor initiation and can cause relapses. At the time point of tumor initiation, CSCs originate from either differentiated cells or adult tissue resident stem cells. Due to their importance, several biomarkers that characterize CSCs have been identified and correlated to diagnosis, therapy and prognosis. However, CSCs have been shown to display a high plasticity, which changes their phenotypic and functional appearance. Such changes are induced by chemo- and radiotherapeutics as well as senescent tumor cells, which cause alterations in the tumor microenvironment. Induction of senescence causes tumor shrinkage by modulating an anti-tumorigenic environment in which tumor cells undergo growth arrest and immune cells are attracted. Besides these positive effects after therapy, senescence can also have negative effects displayed post-therapeutically. These unfavorable effects can directly promote cancer stemness by increasing CSC plasticity phenotypes, by activating stemness pathways in non-CSCs, as well as by promoting senescence escape and subsequent activation of stemness pathways. At the end, all these effects can lead to tumor relapse and metastasis. This review provides an overview of the most frequently used CSC markers and their implementation as biomarkers by focussing on deadliest solid (lung, stomach, liver, breast and colorectal cancers) and hematological (acute myeloid leukemia, chronic myeloid leukemia) cancers. Furthermore, it gives examples on how the CSC markers might be influenced by therapeutics, such as chemo- and radiotherapy, and the tumor microenvironment. It points out, that it is crucial to identify and monitor residual CSCs, senescent tumor cells, and the pro-tumorigenic senescence-associated secretory phenotype in a therapy follow-up using specific biomarkers. As a future perspective, a targeted immune-mediated strategy using chimeric antigen receptor based approaches for the removal of remaining chemotherapy-resistant cells as well as CSCs in a personalized therapeutic approach are discussed.

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“…A recent study showed that MDS stem cells can be derived from both CLEC12A‐positive and ‐negative CD34 + CD38 − subpopulations 21 . Moreover, in some AML cases, CLEC12A‐negative stem cells harbour pre‐leukaemic cytogenetic and/or molecular aberrations, and these cells can be a source of LSCs 22,23 . Therefore, ideally, even in cases with high CLEC12A expression, cytogenetic and molecular analyses of sorted stem cell subsets should be performed to select patients eligible for CLEC12A‐targeted therapies.…”

Section: Ds‐amkl (N = 11) Others (N = 21) P‐valuementioning

confidence: 99%

Blast cells in acute megakaryoblastic leukaemia with Down syndrome are characterized by low CLEC12A expression

et al. 2020

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Revisiting CLEC12A as leukaemic stem cell marker in AML: highlighting the necessity of precision diagnostics in patients eligible for targeted therapy

Cited by 10 publications

References 62 publications

Bimodal expression of potential drug target CLL‐1 (CLEC12A) on CD34+ blasts of AML patients

Bimodal expression of potential drug target CLL‐1 (CLEC12A) on CD34+ blasts of AML patients

Cancer Stem Cells—Origins and Biomarkers: Perspectives for Targeted Personalized Therapies

Blast cells in acute megakaryoblastic leukaemia with Down syndrome are characterized by low CLEC12A expression

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