Avoid common mistakes on your manuscript.
Dear Editor,
Advanced systemic mastocytosis (advSM) often occurs with concurrent eosinophilia [1, 2]. Here, we report a case of advSM with associated eosinophilia and the generation of patient-specific induced pluripotent stem cells (iPS cells) as an attractive, personalized approach for compound identification to overcome unresponsiveness to anti-neoplastic treatment.
A 45-year-old male patient was diagnosed with mast cell leukemia (MCL) in February 2018 (Fig. 1A; month 0) and referred to our center in April 2019. Bone marrow (BM) smears at presentation showed 80% mast cell infiltration. Blood counts revealed leukocytosis (white blood cells 19,000/µl) with eosinophilia (51.4%) and anemia (Hb = 8.1 g/dl) but normal platelet counts. Next generation sequencing analysis [3] detected KITS476I (c.1427G > T, 3.1%) and KRASG12V (c.35G > T, 7.3%) mutations. Fluorescent in situ hybridization (FISH) analysis revealed a PDGFRß rearrangement (5q32) in 1% of the interphases, while cytogenetics showed a normal male karyotype (46,XY). Successive treatments with midostaurin, imatinib, and ripretinib from February 2018 to July 2019 (month 0–17) resulted only in brief periods of clinical improvement. From July to August 2019 (month 17–19), he received 2 cycles of cladribine, resulting in partial remission according to IWG-MRT ECNM consensus response criteria [4]. At this time, he was considered for allogeneic stem cell transplantation (allo-SCT) but avoided follow-up visits during the first SARS-CoV-2 pandemic wave.
In May 2020 (month 27), he presented with progressing MCL. Three cycles of cladribine failed to achieve any relevant clinical improvement. Lacking alternative options, allo-SCT from a haploidentical-related donor after conditioning with fludarabine (50 mg/m2), thiotepa (5 mg/m2), and busulfan (0.66 mg/m2) was performed without acute complications. On day 50, post-allo-SCT BM biopsy showed 78% mast cells, and the patient died within a few days due to multiorgan dysfunction.
In parallel to conventional therapy with the aim to identify compounds that would potentially be effective for the patient, we generated iPS cells from the patient´s BM mononuclear cells (Fig. 1A, B). Two iPS cell lines were further studied and displayed the characteristic pluripotent phenotype (Fig. 1C). Karyotype analysis showed no chromosomal abnormalities (Fig. 1D). The KIT S476I mutation was not detected in the iPS cell clones due to the low allele burden. Importantly, iPS cell-derived hematopoietic cells recapitulated the mast cell (CD45+KIThigh) and granulocytic (CD45+CD66b+) bias of the disease (Fig. 1E–H). This allowed us to proceed with the screening of therapeutic compounds within only 2.5 months after iPS cell generation (Fig. 1I). Imatinib (1 µM) and midostaurin (1 µM) were essentially ineffective on CD45+KIT+/high hematopoietic cells, in agreement with the patient’s clinical data. Unfortunately, the patient died before further compound screenings were finalized.
In summary, within 2.5 months, iPS cell-derived patient-specific drug response data were obtained. This highlights iPS cells as a powerful tool for personalized medicine in oncological hematology when anti-malignant treatment options are exhausted. In addition, we expect a library of patient-specific iPS cell lines with SM mutations and automation of iPS cell production to further accelerate the identification of patient tailored therapies [7,8,9].
References
Kluin-Nelemans HC, Reiter A, Illerhaus A et al (2020) Prognostic impact of eosinophils in mastocytosis: analysis of 2350 patients collected in the ECNM Registry. Leukemia 34:1090–1101. https://doi.org/10.1038/S41375-019-0632-4
Arber DA, Orazi A, Hasserjian R et al (2016) The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127:2391–2405. https://doi.org/10.1182/BLOOD-2016-03-643544
Kirschner M, Maurer A, Wlodarski MW et al (2018) Recurrent somatic mutations are rare in patients with cryptic dyskeratosis congenita. Leukemia 32:1762–1767. https://doi.org/10.1038/S41375-018-0125-X
Gotlib J, Pardanani A, Akin C et al (2013) International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis. Blood 121:2393–2401. https://doi.org/10.1182/BLOOD-2012-09-458521
Liu Y, Wang Y, Gao Y et al (2015) Efficient generation of megakaryocytes from human induced pluripotent stem cells using food and drug administration-approved pharmacological reagents. Stem Cells Transl Med 4:309–319. https://doi.org/10.5966/sctm.2014-0183
Satoh T, Toledo MAS, Boehnke J et al (2021) Human DC3 antigen presenting dendritic cells from induced pluripotent stem cells. Front Cell Dev Biol 9:667304. https://doi.org/10.3389/fcell.2021.667304
Toledo MAS, Gatz M, Sontag S et al (2021) Nintedanib targets KIT D816V neoplastic cells derived from induced pluripotent stem cells of systemic mastocytosis. Blood 137:2070–2084. https://doi.org/10.1182/blood.2019004509
Ma Z, Toledo MAS, Wanek P et al (2022) Cell cluster sorting in automated differentiation of patient-specific induced pluripotent stem cells towards blood cells. Front Bioeng Biotechnol 10:755983. https://doi.org/10.3389/fbioe.2022.755983
Elanzew A, Nießing B, Langendoerfer D et al (2020) The StemCellFactory: a modular system integration for automated generation and expansion of human induced pluripotent stem cells. Front Bioeng Biotechnol 8:1155. https://doi.org/10.3389/fbioe.2020.580352
Funding
Open Access funding enabled and organized by Projekt DEAL.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Ethical approval
Bone marrow sample was obtained after written informed consent (RWTH Aachen University Hospital ethics board reference number EK206/09).
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Marcelo A. S. Toledo and Martin Zenke are joint senior authors.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Atakhanov, S., Christen, D., Rolles, B. et al. Towards personalized medicine with iPS cell technology: a case report of advanced systemic mastocytosis with associated eosinophilia. Ann Hematol 101, 2533–2536 (2022). https://doi.org/10.1007/s00277-022-04975-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-022-04975-9