Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Jul;109(1):50-57.
doi: 10.1111/ejh.13768. Epub 2022 Mar 23.

Multistep pathogenesis of chronic myelomonocytic leukemia in patients

Klaus Geissler  1   2 , Eva Jäger  3 , Agnes Barna  4 , Michael Gurbisz  3 , Renate Marschon  5 , Temeida Graf  2 , Thomas Nösslinger  6 , Michael Pfeilstöcker  6 , Sigrid Machherndl-Spandl  7 , Reinhard Stauder  8 , Armin Zebisch  9   10 , Heinz Sill  9 , Leopold Öhler  11 , Rajko Kusec  12 , Gregor Hoermann  13 , Peter Valent  14   15
Affiliations

Multistep pathogenesis of chronic myelomonocytic leukemia in patients

Klaus Geissler et al. Eur J Haematol. 2022 Jul.

Abstract

Background: A multistep pathogenesis of myeloid leukemia including mutations in epigenetic, spliceosome, and signaling genes has been recently demonstrated in a preclinical model but is poorly validated in patients.

Methods: Clinical, phenotypic, and biologic features were compared between three distinct molecularly defined CMML cohorts including TET2 monomutated patients (T, n = 10), TET2/SRSF2 bimutated patients (TS, n = 19), and patients who had NRAS mutations in addition to TET2/SRSF2 comutations (TSN, n = 14).

Results: Median survival was 90, 45, and 9 months, respectively (p = .001). Whereas no patient in the T and TS group transformed into acute myeloid leukemia (AML), 6/14 patients in the TSN group had AML at study entry or transformed during follow-up. Leukocyte counts, blast cell counts, and LDH levels were significantly higher in TSN vs. TS and T, respectively, whereas hemoglobin and platelet values were not significantly different. Increased growth factor-independent myeloid colony formation was restricted to TSN but not found in T and TS, respectively. The proportion of patients showing in vitro myelomonocytic skewing in T, TS, and TSN was 0%, 56%, and 100%, respectively (p = .010).

Conclusion: Our results demonstrate that the model of multistep pathogenesis in CMML can be recapitulated in patients regarding clinical, phenotypic, and biologic features.

Keywords: CMML; NRAS; SRSF2; TET2; pathogenesis.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Overall survival indicated by Kaplan‐Meier plots in three distinct molecularly defined CMML cohorts including TET2 monomutated patients (T, n = 10), TET2/SRSF2 bimutated patients (TS, n = 19), and patients who had NRAS mutations in addition to TET2/SRSF2 comutations (TSN, n = 14)
FIGURE 2
FIGURE 2
Time to AML transformation in three distinct molecularly defined CMML cohorts including TET2 monomutated patients (T, n = 10), TET2/SRSF2 bimutated patients (TS, n = 19), and patients who had NRAS mutations in addition to TET2/SRSF2 comutations (TSN, n = 14)
FIGURE 3
FIGURE 3
Box plots showing the distribution of spontaneous colony numbers in the three patient cohorts including median values, minimum values, and maximum values, respectively. Cultures were plated in duplicates at 25–100 × 103 PBMNC/ml. Aggregates with more than 40 translucent, dispersed cells were counted as CFU‐GM. CFU‐GM data from patients are expressed as mean values from cultures
See this image and copyright information in PMC

References

    1. Wang T, Pine AR, Kotini AG, et al. Sequential CRISPR gene editing in human IPSCs charts the clonal evolution of myeloid leukemia and identifies early disease targets. Cell Stem Cell. 2021;28(6):1074‐1089.e7. doi:10.1016/j.stem.2021.01.011 - DOI - PMC - PubMed
    1. Geissler K, Jäger E, Barna A, et al. The Austrian biodatabase for chronic myelomonocytic leukemia (ABCMML): a representative and useful real‐life data source for further biomedical research. Wien Klin Wochenschr. 2019;131(17–18):410‐418. doi:10.1007/s00508-019-1526-1 - DOI - PMC - PubMed
    1. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100(7):2292‐2302. doi:10.1182/blood-2002-04-1199 - DOI - PubMed
    1. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5):937‐951. doi:10.1182/blood-2009-03-209262 - DOI - PubMed
    1. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391‐2405. doi:10.1182/blood-2016-03-643544 - DOI - PubMed

Substances