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Correlation of RAS-Pathway Mutations and Spontaneous Myeloid Colony Growth with Progression and Transformation in Chronic Myelomonocytic Leukemia—A Retrospective Analysis in 337 Patients

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
6
Department of Laboratory Medicine, Hospital Hietzing, 1130 Vienna, Austria
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Department of Internal Medicine IV, Hospital Wels-Grieskirchen, 4600 Wels, 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
9
Internal Medicine V with Hematology and Oncology, Medical University of Innsbruck, 6020 Innsbruck, Austria
10
Department of Internal Medicine, Division of Hematology, Medical University of Graz, 8036 Graz, Austria
11
Otto-Loewi-Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, 8036 Graz, Austria
12
Department of Internal Medicine, Hospital Kirchdorf, 4560 Kirchdorf, Austria
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Department of Internal Medicine/Oncology, St. Josef Hospital, 1130 Vienna, Austria
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Department of Internal Medicine, Hospital Horn, 3580 Horn, Austria
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School of Medicine, University of Zagreb, University Hospital Dubrava, 10000 Zagreb, Croatia
16
Department of Hematology, Oncology, and Clinical Immunology, Heinrich-Heine-University, 40225 Düsseldorf, Germany
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Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria
18
Central Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Innsbruck, 6020 Innsbruck, Austria
19
Ludwig Boltzmann Institute for Hematology and Oncology (LBI HO), Medical University of Vienna, 1090 Vienna, Austria
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(8), 3025; https://doi.org/10.3390/ijms21083025
Received: 5 April 2020 / Revised: 19 April 2020 / Accepted: 22 April 2020 / Published: 24 April 2020
(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia 2.0)
Although the RAS-pathway has been implicated as an important driver in the pathogenesis of chronic myelomonocytic leukemia (CMML) a comprehensive study including molecular and functional analyses in patients with progression and transformation has not been performed. A close correlation between RASopathy gene mutations and spontaneous in vitro myeloid colony (CFU-GM) growth in CMML has been described. Molecular and/or functional analyses were performed in three cohorts of 337 CMML patients: in patients without (A, n = 236) and with (B, n = 61) progression/transformation during follow-up, and in patients already transformed at the time of sampling (C, n = 40 + 26 who were before in B). The frequencies of RAS-pathway mutations (variant allele frequency ≥ 20%) in cohorts A, B, and C were 30%, 47%, and 71% (p < 0.0001), and of high colony growth (≥20/105 peripheral blood mononuclear cells) 31%, 44%, and 80% (p < 0.0001), respectively. Increases in allele burden of RAS-pathway mutations and in numbers of spontaneously formed CFU-GM before and after transformation could be shown in individual patients. Finally, the presence of mutations in RASopathy genes as well as the presence of high colony growth prior to transformation was significantly associated with an increased risk of acute myeloid leukemia (AML) development. Together, RAS-pathway mutations in CMML correlate with an augmented autonomous expansion of neoplastic precursor cells and indicate an increased risk of AML development which may be relevant for targeted treatment strategies. View Full-Text
Keywords: CMML; AML; RAS-pathway mutations; CFU-GM CMML; AML; RAS-pathway mutations; CFU-GM
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MDPI and ACS Style

Geissler, K.; Jäger, E.; Barna, A.; Gurbisz, M.; Graf, T.; Graf, E.; Nösslinger, T.; Pfeilstöcker, M.; Tüchler, H.; Sliwa, T.; Keil, F.; Geissler, C.; Heibl, S.; Thaler, J.; Machherndl-Spandl, S.; Zach, O.; Weltermann, A.; Bettelheim, P.; Stauder, R.; Zebisch, A.; Sill, H.; Schwarzinger, I.; Schneeweiss, B.; Öhler, L.; Ulsperger, E.; Kusec, R.; Germing, U.; Sperr, W.R.; Knöbl, P.; Jäger, U.; Hörmann, G.; Valent, P. Correlation of RAS-Pathway Mutations and Spontaneous Myeloid Colony Growth with Progression and Transformation in Chronic Myelomonocytic Leukemia—A Retrospective Analysis in 337 Patients. Int. J. Mol. Sci. 2020, 21, 3025. https://doi.org/10.3390/ijms21083025

AMA Style

Geissler K, Jäger E, Barna A, Gurbisz M, Graf T, Graf E, Nösslinger T, Pfeilstöcker M, Tüchler H, Sliwa T, Keil F, Geissler C, Heibl S, Thaler J, Machherndl-Spandl S, Zach O, Weltermann A, Bettelheim P, Stauder R, Zebisch A, Sill H, Schwarzinger I, Schneeweiss B, Öhler L, Ulsperger E, Kusec R, Germing U, Sperr WR, Knöbl P, Jäger U, Hörmann G, Valent P. Correlation of RAS-Pathway Mutations and Spontaneous Myeloid Colony Growth with Progression and Transformation in Chronic Myelomonocytic Leukemia—A Retrospective Analysis in 337 Patients. International Journal of Molecular Sciences. 2020; 21(8):3025. https://doi.org/10.3390/ijms21083025

Chicago/Turabian Style

Geissler, Klaus, Eva Jäger, Agnes Barna, Michael Gurbisz, Temeida Graf, Elmir Graf, Thomas Nösslinger, Michael Pfeilstöcker, Heinz Tüchler, Thamer Sliwa, Felix Keil, Christoph Geissler, Sonja Heibl, Josef Thaler, Sigrid Machherndl-Spandl, Otto Zach, Ansgar Weltermann, Peter Bettelheim, Reinhard Stauder, Armin Zebisch, Heinz Sill, Ilse Schwarzinger, Bruno Schneeweiss, Leopold Öhler, Ernst Ulsperger, Rajko Kusec, Ulrich Germing, Wolfgang R. Sperr, Paul Knöbl, Ulrich Jäger, Gregor Hörmann, and Peter Valent. 2020. "Correlation of RAS-Pathway Mutations and Spontaneous Myeloid Colony Growth with Progression and Transformation in Chronic Myelomonocytic Leukemia—A Retrospective Analysis in 337 Patients" International Journal of Molecular Sciences 21, no. 8: 3025. https://doi.org/10.3390/ijms21083025

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