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Acute myeloid leukemia

Male predominance in AML is associated with specific preleukemic mutations

Leukemia volume 35, pages 867–870 (2021)Cite this article

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Most cases of acute myeloid leukemia (AML) involve the acquisition of recurrent mutations, and the subsequent clonal expansion of mutant hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM). These are termed preleukemic mutations (pLM), and HSPCs that carry them are still capable of multi-lineage differentiation [1]. Subsequent events, called leukemic mutations, lead to aberrant differentiation and BM failure [2, 3]. We define pLMs by the following criteria: (1) Somatic mutations that are found in leukemic blasts as well as in hematopoietic progenitors and mature cells from different lineages that share a common ancestral stem cell. (2) Somatic mutations which were identified in the hematopoietic system of healthy individuals and are also recurrently found in myeloid malignancies. On the other hand, leukemic and late mutations are somatic mutations that are only present in the leukemic blasts and are absent in normal hematopoietic cells. These mutations cannot be found in healthy individuals [4]. The frequency of AML increases exponentially after 60 years of age, and from reasons yet unknown, is significantly more common in males than in females [5, 6]. Moreover, the male predominance of AML increases with age [5]. In addition, the mutational and cytogenetic profile of young patients is markedly different from that of old adult patients [7]. These observations may point to an association of gender and the occurrence of specific mutations, in the early stages of the development of the disease. In the current study, we analyzed AML and myelodysplastic syndrome (MDS) cases from the COSMIC database [8], as well as a cohort of AML and MDS samples from Münchner Leukämielabor GmbH (MLL), Germany, for bias in somatic variants related to gender.

We used the following files from COSMIC database, release v89, 15th May 2019:

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Fig. 1: Gene counts in males and females of combined sets (COSMIC and MLL, Germany) AML and MDS samples.
Fig. 2: Histograms, densities, and cumulative counts per gender in AML gender-biased genes from COSMIC samples mark distinct frequency patterns across genders and age.

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Acknowledgements

This research was supported by the EU horizon 2020 grant project MAMLE ID: 714731, LLS Grant ID: RTF6005-19, IMOS-712843, ISF IPMP grant ID 3165/19 and ISF-NSF grant ID 2427/18 awarded to LIS. LIS is an incumbent of the Ruth and Louis Leland career development chair. N.K. is an incumbent of the Applebaum Foundation Research Fellow Chair. This research was also supported by the Sagol Institute for Longevity Research, the Barry and Eleanore Reznik Family Cancer Research Fund, Steven B. Rubenstein Research Fund for Leukemia and Other Blood Disorders, the Rising Tide Foundation and the Applebaum Foundation. This work was supported by the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine supporting LIS.

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Authors and Affiliations

  1. Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

    Aviv De-Morgan & Liran Shlush

  2. MLL Munich Leukemia Laboratory, Munich, Germany

    Manja Meggendorfer & Claudia Haferlach

  3. Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, ON, Canada

    Liran Shlush

  4. Division of Hematology, Rambam Healthcare Campus, Haifa, Israel

    Liran Shlush

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  1. Aviv De-Morgan
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  2. Manja Meggendorfer
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  4. Liran Shlush
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Contributions

ADM designed the study, analyzed data, and wrote the paper, MM analyzed data, CH analyzed data, LIS designed the study, wrote the paper, and oversaw the research.

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Correspondence to Liran Shlush.

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CH has equity ownership of MLL Munich Leukemia Laboratory.

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De-Morgan, A., Meggendorfer, M., Haferlach, C. et al. Male predominance in AML is associated with specific preleukemic mutations. Leukemia 35, 867–870 (2021). https://doi.org/10.1038/s41375-020-0935-5

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