Relationship between CD34/CD38 and side population (SP) defined leukemia stem cell compartments in acute myeloid leukemia

Moshaver, Bijan; Wouters, Rolf; Ossenkoppele, Gert J.; Westra, Guus; Kwidama, Zinia J.; Rutten, Arjo P.; Kaspers, Gertjan J. L.; Cloos, Jacqueline; Schuurhuis, Gerrit Jan

doi:10.1016/j.leukres.2019.04.004

Cited by 13 publications

(11 citation statements)

References 28 publications

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“…ABCG2 could be a promising therapeutic target for the eradication of leukemia stem cells (LSCs) (9), based on the evidence that ABCG2 was responsible for the identification and isolation of the 'side population' (SP) phenotype using flow cytometry, due to the efflux of Hoechst 33342 from tumor cells, with cancer stem cell characteristics (10). SP cells are highly rich in LSCs, which are responsible for asymmetric cell division, self-renewal capacity and the maintenance of leukemia (11,12). Furthermore, ABCG2 facilitated the effusion of antineoplastic agents out of LSCs and plays a crucial role in the differentiation, proliferation and self-renewal of LSCs (13,14).…”

Section: Introductionmentioning

confidence: 99%

In vitro and ex vivo anti‑tumor effect and mechanism of Tucatinib in leukemia stem cells and ABCG2‑overexpressing leukemia cells

et al. 2020

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Leukemia stem cells (LSCs), which evade standard chemotherapy, may lead to chemoresistance and disease relapse. The overexpression of ATP-binding cassette subfamily G member 2 (ABCG2) is an important determinant of drug resistance in LSCs and it can serve as a marker for LSCs. Targeting ABCG2 is a potential strategy to selectively treat and eradicate LSCs, and, hence, improve leukemia therapy. Tucatinib (Irbinitinib) is a novel tyrosine kinase inhibitor, targeting ErbB family member HER2, and was approved by the Food and Drug Administration in April 2020, and in Switzerland in May 2020 for the treatment of HER2-positive breast cancer. In the present study, the results demonstrated that tucatinib significantly improved the efficacy of conventional chemotherapeutic agents in ABCG2-overexpressing leukemia cells and primary leukemia blast cells, derived from patients with leukemia. In addition, tucatinib markedly decreased the proportion of leukemia stem cell-like side population (SP) cells. In SP cells, isolated from leukemia cells, the intracellular accumulation of Hoechst 33342, which is an ABCG2 substrate, was significantly elevated by tucatinib. Furthermore, tucatinib notably inhibited the efflux of [ 3 H]-mitoxantrone and, hence, there was a higher level of [ 3 H]-mitoxantrone in the HL60/ABCG2 cell line. The result from the ATPase assay revealed that tucatinib may interact with the drug substrate-binding site and stimulated ATPase activity of ABCG2. However, the protein expression level and cellular location of ABCG2 were not affected by tucatinib treatment. Taken together, these data suggested that tucatinib could sensitize conventional chemotherapeutic agents, in ABCG2-overexpressing leukemia cells and LSCs, by blocking the pump function of the ABCG2 protein. The present study revealed that combined treatment with tucatinib and conventional cytotoxic agents could be a potential therapeutic strategy in ABCG2-positive leukemia.

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Section: Introductionmentioning

confidence: 99%

In vitro and ex vivo anti‑tumor effect and mechanism of Tucatinib in leukemia stem cells and ABCG2‑overexpressing leukemia cells

et al. 2020

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“…A recent study concerning the relationships between CD34 with NPM1 mut or FLT3 ‐ITD described the distribution of FLT3 ‐ITD high almost exclusively in the CD34 (+) group and rarely in the CD34 (−) group, the latter entirely presenting FLT3 ‐ITD low features. 37 Thus, CD34 negativity may likely imply an absence of FLT3 ‐ITD or low AR, which partly explains the better prognosis of CD34 (−) patients than those with CD34 (+) . Our findings indicate that ID‐Ara‐C as a first‐line induction in NPM1 mut / FLT3 ‐ITD (+) patients improved the remission rate, especially for CD34 (+) patients at the initial diagnosis.…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, AR was detected in only some NPM1 mut / FLT3 ‐ITD (+) patients, so we did not include FLT3 ‐ITD AR in the analysis. A recent study concerning the relationships between CD34 with NPM1 mut or FLT3 ‐ITD described the distribution of FLT3 ‐ITD high almost exclusively in the CD34 (+) group and rarely in the CD34 (−) group, the latter entirely presenting FLT3 ‐ITD low features 37 . Thus, CD34 negativity may likely imply an absence of FLT3 ‐ITD or low AR, which partly explains the better prognosis of CD34 (−) patients than those with CD34 (+) .…”

Section: Discussionmentioning

confidence: 99%

Prognostication refinement in NPM1‐mutated acute myeloid leukemia stratified by FLT3‐ITD status with different induction doses of cytarabine

et al. 2023

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Objective We aimed to retrospectively discern the heterogeneity of outcomes from clinicopathological characteristics and next‐generation sequencing (NGS) data in adult patients with NPM1‐ mutated ( NPM1 mut ) acute myeloid leukemia (AML) induced with standard‐dose (SD, 100–200 mg/m 2 ) and intermediate‐dose (ID, 1000–2000 mg/m 2 ) cytarabine arabinose (Ara‐C). Methods In the entire cohort and FLT3 ‐ITD subgroups, multivariate Logistic and Cox regression analyses were used to analyze the comprehensive complete remission (cCR) rate after one or two induction cycles, event‐free survival (EFS), and overall survival (OS). Results Among a total of 203 NPM1 mut patients evaluable for clinical outcome, 144 (70.9%) received a first SD‐Ara‐C induction and 59 (29.1%) received ID‐Ara‐C induction. Early death was recorded in seven (3.4%) after one or two cycles of induction. Focusing analysis on the NPM1 mut / FLT3 ‐ITD (−) subgroup, independent factors showing inferior outcome were presence of TET2 mutation [cCR rate, OR = 12.82 (95%CI 1.93–85.28), p = 0.008; EFS, HR = 2.92 (95%CI 1.46–5.86), p = 0.003], increasing age [EFS, HR = 1.49 (95%CI 1.10–2.02), p = 0.012 by every 10‐years elevation], white blood cell count ≥60 × 10 9 /L [EFS, HR = 3.30 (95%CI 1.63–6.70), p = 0.001], and ≥4 mutated genes at initial diagnosis [OS, HR = 5.54 (95%CI 1.77–17.33), p = 0.003]. In contrast, when focusing on the NPM1 mut / FLT3 ‐ITD (+) subgroup, factors showing superior outcome were ID‐Ara‐C induction [cCR rate, OR = 0.20 (95%CI 0.05–0.81), p = 0.025; EFS, HR = 0.27 (95%CI 0.13–0.60), p = 0.001] and allo‐transplantation [OS, HR = 0.45 (95%CI 0.21–0.94), p = 0.033]. Factors showing inferior outcome included CD34 (+) [cCR rate, OR = 6.22 (95%CI 1.86–20.77), p = 0.003; EFS, HR = 2.01 (95%CI 1.12–3.61), p = 0.020] and ≥5 mutated genes [OS, HR = 2.85 (95%CI 1.33–6.10), p = 0.007]. Conclusion We conclude that TET2 (+) , age, and white blood cell count convey an outcome risk modulation for AML with NPM1 mut / FLT3 ‐ITD (−) , as does CD34 and ...

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“…Another potential way to improve the prognostic significance of MRD assessment is by adding information on leukemic stem cells (LSCs). LSCs, which are defined by CD34/CD38 expression among other antigens in the flowcytometric analysis of leukemia, seem critical for the development of AML and for relapse-initiation, because LSCs seem to have increased drug resistance and have self-renewal capacity at the same time [32]. Especially the side population (SP) was shown to have leukemia-initiating ability and harbored the strongest functional stem cell activity in CD34+ and CD34-AML.…”

Section: Discussionmentioning

confidence: 99%

Measurable residual disease in pediatric acute myeloid leukemia: a systematic review

Segerink

Haas

Kaspers

2021

Expert Review of Anticancer Therapy

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Introduction: A systematic review was performed to assess the prognostic value of Measurable Residual Disease (MRD) during treatment, for relapse and overall survival in pediatric acute myeloid leukemia (AML). Areas covered: A systematic search of available literature was performed to identify original full-text articles concerning MRD as prognostic for relapse and survival in pediatric AML. Thirteen studies were included, and in all studies, MRD positivity during treatment was associated with worse clinical outcome. MRD positivity was significantly associated with a higher probability of relapse in eleven studies. However, MRD negativity does not exclude the possibility of relapse in pediatric AML, while positivity early during therapy does not exclude cure. Expert opinion: MRD positivity during treatment has emerged as the most powerful prognostic factor in pediatric AML concerning relapse and overall survival and is useful for risk-group adapted treatment. Future studies should identify the optimal time-point(s) for MRD measurements and the optimal technique, to further improve its prognostic significance.

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Relationship between CD34/CD38 and side population (SP) defined leukemia stem cell compartments in acute myeloid leukemia

Cited by 13 publications

References 28 publications

In vitro and ex vivo anti‑tumor effect and mechanism of Tucatinib in leukemia stem cells and ABCG2‑overexpressing leukemia cells

In vitro and ex vivo anti‑tumor effect and mechanism of Tucatinib in leukemia stem cells and ABCG2‑overexpressing leukemia cells

Prognostication refinement in NPM1‐mutated acute myeloid leukemia stratified by FLT3‐ITD status with different induction doses of cytarabine

Measurable residual disease in pediatric acute myeloid leukemia: a systematic review

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