<scp>CD</scp>45<scp>RA</scp>, a specific marker for leukaemia stem cell sub‐populations in acute myeloid leukaemia

Kersten, Bas; Valkering, Matthijs; Wouters, Rolf; Amerongen, Rosa van; Hanekamp, Diana; Kwidama, Zinia J.; Valk, Peter J.M.; Ossenkoppele, Gert J.; Zeijlemaker, Wendelien; Kaspers, Gertjan J. L.; Cloos, Jacqueline; Schuurhuis, Gerrit Jan

doi:10.1111/bjh.13941

Cited by 53 publications

(44 citation statements)

References 37 publications

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“…We then investigated CD9 expression on normal hematopoietic progenitors (HSCs) and on their leukemic counterparts (LSCs) to use CD9 as a marker of MRD in the most immature compartment. We studied progenitor cell populations based on the expression of the following antigens: HSC (CD34+CD38−CD45RA−CD90+), Multipotent Progenitors (MPP: CD34+CD38−CD45RA−CD90dim), Lymphoid‐Primed Multipotent Progenitors (LMPP: CD34+CD38−CD45RA+CD90−), and the putative LSCs (CD34+CD38−) which harbored various patterns of expression of CD90 and CD45RA . These phenotypic definitions of progenitor cells have been previously verified in functional assays …”

Section: Resultsmentioning

confidence: 99%

“…Over the past few years, various markers have been described to better characterize LSC or blast cells from AML with normal cytogenetics (CN‐AML) for minimal residual disease (MRD) monitoring . Furthermore, targeting MRD by multiparametric flow cytometry (MFC) to monitor treatment efficiency is one of the greatest challenges in the treatment of AML.…”

Section: Introductionmentioning

confidence: 99%

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CD9 in acute myeloid leukemia: Prognostic role and usefulness to target leukemic stem cells

et al. 2019

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CD9 is a cell surface protein and belongs to the tetraspanin family. Its role in carcinomagenesis has been widely studied in solid tumors but remains controversial, depending on the cancer type. Although CD9 seems to be associated with unfavorable outcome and disease progression in acute lymphoblastic leukemia (ALL), this marker has not yet been studied in acute myeloid leukemia (AML). First, we explored its prognostic role and its association with biological factors in a cohort of 112 AML patients treated with intensive chemotherapy. CD9 was expressed in 40% of AML and was associated with a favorable outcome (event‐free survival and relapse‐free survival) in univariate (P = 0.009 and P = 0.048, respectively) and multivariate (P = 0.004 and P = 0.039, respectively) analyses. Interestingly, CD9 expression was different between the more immature physiologic and AML cells (CD34+CD38−) as it was also expressed in AML on putative leukemic stem cells (LSCs) but not on hematopoietic stem cells (HSCs). Hence, CD9 could be a very relevant marker for minimal residual disease (MRD) monitoring in AML based on LSC targeting.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CD9 in acute myeloid leukemia: Prognostic role and usefulness to target leukemic stem cells

et al. 2019

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“…Using such specific leukemia associated LSC immunophenotypes enables detection of LSCs in the vast majority of CD34 positive AML cases (Hanekamp, Cloos, & Schuurhuis, ). LSCs, as defined as aberrant marker positive CD34+CD38− cells, harbor specific molecular aberrancies (e.g., FLT3‐ITD, NPM1 mut ) and thus are indeed leukemic cells (Kersten et al., ; Schuurhuis et al., ; Terwijn et al., ).…”

Section: Commentarymentioning

confidence: 99%

Immunophenotypic Detection of Measurable Residual (Stem Cell) Disease Using LAIP Approach in Acute Myeloid Leukemia

2019

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Half of the patients with acute myeloid leukemia (AML), who achieve complete remission after chemotherapy treatment, will ultimately experience a relapse. Measurable residual disease (MRD) is an important post‐treatment risk factor in AML, because it gives additional information about the depth of the remission. Within MRD, the small population of leukemic stem cells (LSCs) is thought to be at the base of the actual relapse. In this protocol, the flow cytometric detection of MRD and LSCs herein is outlined. We give a detailed overview of the sampling procedures for optimal multiparameter flow cytometry assessment of both MRD and LSC, using leukemia associated immunophenotypes (LAIPs) and LSC markers. Moreover, an overview of the gating strategies to detect LAIPs and LSC markers is provided. This protocol serves as guidance for flow cytometric detection of measurable residual (stem cell) disease necessary for proper therapeutic decision making in AML patients. © 2019 The Authors. Basic Protocol 1: Immunophenotypic LAIP detection for measurable residual disease monitoring Basic Protocol 2: Immunophenotypic detection of CD34+CD38− leukemic stem cells

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“…Both CD44 and GPR56 were expressed on >90% of CD34 + 38 − HSPCs, while the markers CD117, CD305, CD47 and CD33 were prevalent in substantial numbers of normal HSPCs with a surface expression on 50%-90% of cells, comparably to what has been reported. [21][22][23][24][25][26][27][28] The remaining markers were hardly expressed on CD34 + 38 − HSPCs ( Figure 1B).…”

Section: Mfc Analysis Of Cell Surface Markers For Residual Leukemicmentioning

confidence: 99%

“…Since no single marker showed an ideal expression profile for leukemic cell enrichment, we aimed to determine the best marker combination enabling enrichment of residual leukemic cells in a maximum number of AML cases. Although CD47, GPR56, CD33, CD305 and CD45RA were expressed on >90% blasts of the majority of AML cases evaluated, these markers were not considered further for enrichment, because they were also widely expressed on normal hematopoietic cell subtypes including CD34 + 38 − HSPCs [21][22][23][24][25] ( Figure 1B and Figure S2). From that perspective CLL-1, TIM-3, CD117 and CD123 were the most promising markers, since they were only expressed on either a distinct progenitor population or on small subtypes of mature leukocytes.…”

Section: Mfc Analysis Of Cell Surface Markers For Residual Leukemicmentioning

confidence: 99%

Sensitive and broadly applicable residual disease detection in acute myeloid leukemia using flow cytometry‐based leukemic cell enrichment followed by mutational profiling

et al. 2020

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Persistent measurable residual disease (MRD) is an increasingly important prognostic marker in acute myeloid leukemia (AML). Currently, MRD is determined by multi‐parameter flow cytometry (MFC) or PCR‐based methods detecting leukemia‐specific fusion transcripts and mutations. However, while MFC is highly operator‐dependent and difficult to standardize, PCR‐based methods are only available for a minority of AML patients. Here we describe a novel, highly sensitive and broadly applicable method for MRD detection by combining MFC‐based leukemic cell enrichment using an optimized combinatorial antibody panel targeting CLL‐1, TIM‐3, CD123 and CD117, followed by mutational analysis of recurrently mutated genes in AML. In dilution experiments this method showed a sensitivity of 10−4 to 10−5 for residual disease detection. In prospectively collected remission samples this marker combination allowed for a median 67‐fold cell enrichment with sufficient DNA quality for mutational analysis using next generation sequencing (NGS) or digital PCR in 39 out of 41 patients. Twenty‐one samples (53.8%) tested MRD positive, whereas 18 (46.2%) were negative. With a median follow‐up of 559 days, 71.4% of MRD positive (15/21) and 27.8% (5/18) of MRD negative patients relapsed (P = .007). The cumulative incidence of relapse (CIR) was higher for MRD positive patients (5‐year CIR: 90.5% vs 28%, P < .001). In multivariate analysis, MRD positivity was a prominent factor for CIR. Thus, MFC‐based leukemic cell enrichment using antibodies against CLL‐1, TIM‐3, CD123 and CD117 followed by mutational analysis allows high sensitive MRD detection and is informative on relapse risk in the majority of AML patients.

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CD45RA, a specific marker for leukaemia stem cell sub‐populations in acute myeloid leukaemia

Cited by 53 publications

References 37 publications

CD9 in acute myeloid leukemia: Prognostic role and usefulness to target leukemic stem cells

CD9 in acute myeloid leukemia: Prognostic role and usefulness to target leukemic stem cells

Immunophenotypic Detection of Measurable Residual (Stem Cell) Disease Using LAIP Approach in Acute Myeloid Leukemia

Sensitive and broadly applicable residual disease detection in acute myeloid leukemia using flow cytometry‐based leukemic cell enrichment followed by mutational profiling

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