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Article

Molecular Basis and Clinical Application of Growth-Factor-Independent In Vitro Myeloid Colony Formation in Chronic Myelomonocytic Leukemia

1
Medical School, Sigmund Freud University, 1020 Vienna, Austria
2
Department of Internal Medicine V with Hematology, Oncology and Palliative Medicine, Hospital Hietzing, 1130 Vienna, Austria
3
Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria
4
Blood Transfusion Service, Blood Transfusion Service for Upper Austria, Austrian Red Cross, 4020 Linz, Austria
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Department of Internal Medicine III, Hanusch Hospital, 1140 Vienna, Austria
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Department of Internal Medicine I with Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz Barmherzige Schwestern—Elisabethinen, 4020 Linz, Austria
7
Internal Medicine V with Hematology and Oncology, Medical University of Innsbruck, 6020 Innsbruck, Austria
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Department of Internal Medicine, Division of Hematology, Medical University of Graz, 8036 Graz, Austria
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Department of Internal Medicine/Oncology, St. Josef Hospital, 1130 Vienna, Austria
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School of Medicine, University of Zagreb, University Hospital Dubrava, 10000 Zagreb, Croatia
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Central Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Innsbruck, 6020 Innsbruck, Austria
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Ludwig Boltzmann Institute for Hematology and Oncology (LBI HO), Medical University of Vienna, 1090 Vienna, Austria
13
Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(17), 6057; https://doi.org/10.3390/ijms21176057
Received: 26 July 2020 / Revised: 20 August 2020 / Accepted: 21 August 2020 / Published: 22 August 2020
(This article belongs to the Special Issue Stem Cell Biology of Myeloid Neoplasms)
We have originally reported that colony-forming units granulocyte/macrophage (CFU-GM) formation is an in vitro feature of chronic myelomonocytic leukemia (CMML) and a strong predictor for short survival. Elucidation of the molecular basis underlying this in vitro phenomenon could be helpful to define molecular features that predict inferior outcome in patients. We studied the correlation between the mutational landscape and spontaneous colony formation in 164 samples from 125 CMML patients. As compared to wildtype samples, spontaneous in vitro CFU-GM formation was significantly increased in samples containing mutations in NRAS, CBL and EZH2 that were confirmed as independent stimulatory factors by multiple regression analysis. Inducible expression of mutated RAS but not JAK2 was able to induce growth factor independence of Ba/F3 cells. Whereas high colony CFU-GM growth was a strong unfavorable parameter for survival (p < 0.00001) and time to transformation (p = 0.01390), no single mutated gene had the power to significantly predict for both outcome parameters. A composite molecular parameter including NRAS/CBL/EZH2, however, was predictive for inferior survival (p = 0.00059) as well as for increased risk of transformation (p = 0.01429). In conclusion, we show that the composite molecular profile NRAS/CBL/EZH2 derived from its impact on spontaneous in vitro myeloid colony formation improves the predictive power over single molecular parameters in patients with CMML. View Full-Text
Keywords: CMML; in vitro cultures; CFU-GM; NGS; prognosis; AML CMML; in vitro cultures; CFU-GM; NGS; prognosis; AML
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MDPI and ACS Style

Geissler, K.; Jäger, E.; Barna, A.; Gurbisz, M.; Graf, T.; Graf, E.; Nösslinger, T.; Pfeilstöcker, M.; Machherndl-Spandl, S.; Stauder, R.; Zebisch, A.; Sill, H.; Öhler, L.; Kusec, R.; Hörmann, G.; Valent, P. Molecular Basis and Clinical Application of Growth-Factor-Independent In Vitro Myeloid Colony Formation in Chronic Myelomonocytic Leukemia. Int. J. Mol. Sci. 2020, 21, 6057. https://doi.org/10.3390/ijms21176057

AMA Style

Geissler K, Jäger E, Barna A, Gurbisz M, Graf T, Graf E, Nösslinger T, Pfeilstöcker M, Machherndl-Spandl S, Stauder R, Zebisch A, Sill H, Öhler L, Kusec R, Hörmann G, Valent P. Molecular Basis and Clinical Application of Growth-Factor-Independent In Vitro Myeloid Colony Formation in Chronic Myelomonocytic Leukemia. International Journal of Molecular Sciences. 2020; 21(17):6057. https://doi.org/10.3390/ijms21176057

Chicago/Turabian Style

Geissler, Klaus, Eva Jäger, Agnes Barna, Michael Gurbisz, Temeida Graf, Elmir Graf, Thomas Nösslinger, Michael Pfeilstöcker, Sigrid Machherndl-Spandl, Reinhard Stauder, Armin Zebisch, Heinz Sill, Leopold Öhler, Rajko Kusec, Gregor Hörmann, and Peter Valent. 2020. "Molecular Basis and Clinical Application of Growth-Factor-Independent In Vitro Myeloid Colony Formation in Chronic Myelomonocytic Leukemia" International Journal of Molecular Sciences 21, no. 17: 6057. https://doi.org/10.3390/ijms21176057

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