Coexpression profile of leukemic stem cell markers for combinatorial targeted therapy in AML

Haubner, Sascha; Perna, Fabiana; Köhnke, Thomas; Schmidt, Christina; Berman, Samuel H.; Augsberger, Christian; Schnorfeil, Frauke; Krupka, Christina; Lichtenegger, Felix S.; Liu, X.; Kerbs, Paul; Schneider, Stephanie; Metzeler, Klaus H.; Spiekermann, Karsten; Hiddemann, Wolfgang; Greif, Philipp A.; Herold, Tobias; Sadelain, Michel; Subklewe, Marion

doi:10.1038/s41375-018-0180-3

Cited by 240 publications

(276 citation statements)

References 55 publications

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“…Interestingly, CD9 antigen level of expression is identical between LSCs and AML blast cells and is not expressed on normal HSCs. These findings are particularly relevant as the majority of antigens associated with LSCs (ie, TIM3, CLL1, and CD244) are less expressed on these cells compared to bulk cells and are frequently coexpressed on normal HSCs and progenitors . Recently, Coustan‐Smith et al published a study on MRD monitoring in AML by MFC and, interestingly, they found an overexpression of CD9 on blast cells (in 30% of AML cases) compared to physiologic myeloblasts .…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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

et al. 2019

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“…38 Moreover, antigen targeting is an appealing approach in cancer treatment. 29,39 Routinely, leukapheresis products are evaluated by FCM to enumerate CD34 1 cells, and simultaneous evaluation of aberrant CD7 expression on CD38 1 CD34cells would be feasible in most laboratories as performed in diagnostic and MRD settings of AML and MDS, as shown by Zeijlemaker et al 28 Targeted NGS offers the advantage of accurate prediction of which specific mutations confer an actual risk of tMN, albeit this perspective will be consolidated in the future. The accumulating evidence pointing to the increased risk of tMN in patients with CH who are treated with ASCT makes close monitoring with early intervention an alluring and feasible option.…”

Section: Discussionmentioning

confidence: 99%

Clonal hematopoiesis predicts development of therapy-related myeloid neoplasms post–autologous stem cell transplantation

Soerensen¹,

Aggerholm²,

Kerndrup

et al. 2020

Blood Advances

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Therapy-related myeloid neoplasms (tMN) develop after exposure to cytotoxic and radiation therapy, and due to their adverse prognosis, it is of paramount interest to identify patients at high risk. The presence of clonal hematopoiesis has been shown to increase the risk of developing tMN. The value of analyzing hematopoietic stem cells harvested at leukapheresis before autologous stem cell transplantation (ASCT) with next-generation sequencing and immunophenotyping represents potentially informative parameters that have yet to be discovered. We performed a nested case-control study to elucidate the association between clonal hematopoiesis, mobilization potential, and aberrant immunophenotype in leukapheresis products with the development of tMN after ASCT. A total of 36 patients with nonmyeloid disease who were diagnosed with tMN after treatment with ASCT were included as case subjects. Case subjects were identified from a cohort of 1130 patients treated with ASCT and matched with 36 control subjects who did not develop tMN after ASCT. Case subjects were significantly poorer mobilizers of CD34+ cells at leukapheresis (P = .016), indicating that these patients possess inferior bone marrow function. Both clonal hematopoiesis (odds ratio, 5.9; 95% confidence interval, 1.8-19.1; P = .003) and aberrant expression of CD7 (odds ratio, 6.6; 95% confidence interval, 1.6-26.2; P = .004) at the time of ASCT were associated with an increased risk of developing tMN after ASCT. In conclusion, clonal hematopoiesis, present at low variant allele frequencies, and aberrant CD7 expression on stem cells in leukapheresis products from patients with nonmyeloid hematologic cancer hold potential for the early identification of patients at high risk of developing tMN after ASCT.

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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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Coexpression profile of leukemic stem cell markers for combinatorial targeted therapy in AML

Cited by 240 publications

References 55 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

Clonal hematopoiesis predicts development of therapy-related myeloid neoplasms post–autologous stem cell transplantation

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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