Revisiting CLEC12A as leukaemic stem cell marker in AML

highlighting the necessity of precision diagnostics in patients eligible for targeted therapy

Marie Bill*, Anni Aggerholm, Eigil Kjeldsen, Anne S. Roug, Peter Hokland, Line Nederby

*Kontaktforfatter for dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Targeted therapy directed against rare disease-propagating leukaemic stem cells (LSCs) is a promising prospect for improving the outcome of acute myeloid leukaemia (AML) patients. Thus, distinguishing LSCs from normal haematopoietic stem and progenitor cells (HSPCs) is essential. The CLEC12A receptor has been proposed as a specific marker of LSCs, and consequently as an appealing treatment target. To explore the role of CLEC12A in further detail, we investigated whether a sorting strategy based on the activity of aldehyde dehydrogenase and CLEC12A expression could separate residual normal HSPCs from LSCs in bone marrow from 5 AML patients. We demonstrate that this distinction was possible in 2/5 cases, however with evidence of pre-leukaemic mutations in the CLEC12A- stem cells in one case. In contrast, cytogenetic and/or molecular aberrations were detected in both the CLEC12A+/− cell subsets in 3/5 AML cases studied. Furthermore, targeted next generation sequencing (NGS) of the sorted cell subsets revealed a pronounced clonal heterogeneity in the CLEC12A- cells suggestive of the leukaemia often originating in this immature cell subset. In conclusion, we provide proof-of-concept that precision diagnostics employing targeted cytogenetic/NGS-based analyses on highly purified cell subsets could be a powerful tool for selecting patients eligible for LSC-directed therapy.

OriginalsprogEngelsk
TidsskriftBritish Journal of Haematology
Vol/bind184
Udgave nummer5
Sider (fra-til)769-781
ISSN0007-1048
DOI
StatusUdgivet - mar. 2019

Fingeraftryk

Acute Myeloid Leukemia
Cytogenetics
Aldehyde Dehydrogenase
Rare Diseases
Leukemia
Mutation

Citer dette

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title = "Revisiting CLEC12A as leukaemic stem cell marker in AML: highlighting the necessity of precision diagnostics in patients eligible for targeted therapy",
abstract = "Targeted therapy directed against rare disease-propagating leukaemic stem cells (LSCs) is a promising prospect for improving the outcome of acute myeloid leukaemia (AML) patients. Thus, distinguishing LSCs from normal haematopoietic stem and progenitor cells (HSPCs) is essential. The CLEC12A receptor has been proposed as a specific marker of LSCs, and consequently as an appealing treatment target. To explore the role of CLEC12A in further detail, we investigated whether a sorting strategy based on the activity of aldehyde dehydrogenase and CLEC12A expression could separate residual normal HSPCs from LSCs in bone marrow from 5 AML patients. We demonstrate that this distinction was possible in 2/5 cases, however with evidence of pre-leukaemic mutations in the CLEC12A- stem cells in one case. In contrast, cytogenetic and/or molecular aberrations were detected in both the CLEC12A+/− cell subsets in 3/5 AML cases studied. Furthermore, targeted next generation sequencing (NGS) of the sorted cell subsets revealed a pronounced clonal heterogeneity in the CLEC12A- cells suggestive of the leukaemia often originating in this immature cell subset. In conclusion, we provide proof-of-concept that precision diagnostics employing targeted cytogenetic/NGS-based analyses on highly purified cell subsets could be a powerful tool for selecting patients eligible for LSC-directed therapy.",
keywords = "acute myeloid leukaemia, ALDH, hMICL, leukaemic stem cells, precision medicine",
author = "Marie Bill and Anni Aggerholm and Eigil Kjeldsen and Roug, {Anne S.} and Peter Hokland and Line Nederby",
year = "2019",
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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. / Bill, Marie; Aggerholm, Anni; Kjeldsen, Eigil; Roug, Anne S.; Hokland, Peter; Nederby, Line.

I: British Journal of Haematology, Bind 184, Nr. 5, 03.2019, s. 769-781.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Revisiting CLEC12A as leukaemic stem cell marker in AML

T2 - highlighting the necessity of precision diagnostics in patients eligible for targeted therapy

AU - Bill, Marie

AU - Aggerholm, Anni

AU - Kjeldsen, Eigil

AU - Roug, Anne S.

AU - Hokland, Peter

AU - Nederby, Line

PY - 2019/3

Y1 - 2019/3

N2 - Targeted therapy directed against rare disease-propagating leukaemic stem cells (LSCs) is a promising prospect for improving the outcome of acute myeloid leukaemia (AML) patients. Thus, distinguishing LSCs from normal haematopoietic stem and progenitor cells (HSPCs) is essential. The CLEC12A receptor has been proposed as a specific marker of LSCs, and consequently as an appealing treatment target. To explore the role of CLEC12A in further detail, we investigated whether a sorting strategy based on the activity of aldehyde dehydrogenase and CLEC12A expression could separate residual normal HSPCs from LSCs in bone marrow from 5 AML patients. We demonstrate that this distinction was possible in 2/5 cases, however with evidence of pre-leukaemic mutations in the CLEC12A- stem cells in one case. In contrast, cytogenetic and/or molecular aberrations were detected in both the CLEC12A+/− cell subsets in 3/5 AML cases studied. Furthermore, targeted next generation sequencing (NGS) of the sorted cell subsets revealed a pronounced clonal heterogeneity in the CLEC12A- cells suggestive of the leukaemia often originating in this immature cell subset. In conclusion, we provide proof-of-concept that precision diagnostics employing targeted cytogenetic/NGS-based analyses on highly purified cell subsets could be a powerful tool for selecting patients eligible for LSC-directed therapy.

AB - Targeted therapy directed against rare disease-propagating leukaemic stem cells (LSCs) is a promising prospect for improving the outcome of acute myeloid leukaemia (AML) patients. Thus, distinguishing LSCs from normal haematopoietic stem and progenitor cells (HSPCs) is essential. The CLEC12A receptor has been proposed as a specific marker of LSCs, and consequently as an appealing treatment target. To explore the role of CLEC12A in further detail, we investigated whether a sorting strategy based on the activity of aldehyde dehydrogenase and CLEC12A expression could separate residual normal HSPCs from LSCs in bone marrow from 5 AML patients. We demonstrate that this distinction was possible in 2/5 cases, however with evidence of pre-leukaemic mutations in the CLEC12A- stem cells in one case. In contrast, cytogenetic and/or molecular aberrations were detected in both the CLEC12A+/− cell subsets in 3/5 AML cases studied. Furthermore, targeted next generation sequencing (NGS) of the sorted cell subsets revealed a pronounced clonal heterogeneity in the CLEC12A- cells suggestive of the leukaemia often originating in this immature cell subset. In conclusion, we provide proof-of-concept that precision diagnostics employing targeted cytogenetic/NGS-based analyses on highly purified cell subsets could be a powerful tool for selecting patients eligible for LSC-directed therapy.

KW - acute myeloid leukaemia

KW - ALDH

KW - hMICL

KW - leukaemic stem cells

KW - precision medicine

U2 - 10.1111/bjh.15711

DO - 10.1111/bjh.15711

M3 - Journal article

VL - 184

SP - 769

EP - 781

JO - British Journal of Haematology

JF - British Journal of Haematology

SN - 0007-1048

IS - 5

ER -