Moving Beyond Somatic Alterations - Uncovering the Germline Basis of Myeloid Malignancies

Sep 22, 2026

Myeloid neoplasms (MNs) with germline predisposition form a distinct, increasingly recognized category in the WHO framework, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) driven by inherited genetic alterations. Presentations may occur with characteristic cytopenias in younger patients or in adulthood, underscoring vigilance beyond age and family history. Key genes include RUNX1, CEBPA, and RNA splicing or telomere biology regulators. Germline identification guides targeted therapeutic choices, especially HSCT, and supports genetic counseling and surveillance. Accurate diagnosis often requires non-hematopoietic germline DNA testing to enable personalized care.

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CategoryHealthcare

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Pages25

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Review Moving Beyond Somatic Alterations: Uncovering the Germline Basis of Myeloid Malignancies Ismail Elbaz Younes 1, Lynh Nguyen 2 and Ling Zhang 3, * Academic Editor: NunoVale Received: 10 December 2025 Revised: 3 January 2026 Accepted: 4 January 2026 Published: 13 January 2026 Copyright: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA; [elbaz008@umn.edu](elbaz008@umn.edu) 2 Pathology and Laboratory Medicine, James A. Haley Veterans’ Hospital, Tampa, FL 33612, USA 3 Department of Pathology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA * [Correspondence: ling.zhang@moffitt.org](Correspondence: ling.zhang@moffitt.org); Tel.: +1-813-745-2852 Simple Summary Myeloid neoplasms with germline predisposition develop blood cancers, such as AML and MDS, and arise from inherited genetic mutations rather than acquired ones. Individuals born with errors in genes like RUNX1, GATA2, or DDX41 have a significantly increased lifetime risk of developing hematologic malignancies. Identifying hereditary etiology is vital as it influences treatment strategies, including donor selection for stem cell transplant, and necessitates genetic counseling and surveillance for at-risk family members. Abstract Myeloid neoplasms (MNs) with germline predisposition represent a distinct, increasingly recognized category in the WHO classification, encompassing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) arising in the context of an inherited genetic alteration or mutation. While often presenting at a younger age or with characteristic cytopenias with or without organ dysfunction, some can manifest in adulthood, highlighting the need for vigilance regardless of age or family history. Key predisposing genes include transcription factors (e.g., RUNX1, CEBPA) and genes involved in RNA splicing and telomere biology disorders. Identification of these germline mutations is critical as MNs with germline predisposition dictate specific therapeutic strategies—particularly for hematopoietic stem cell transplantation (HSCT)—and require genetic counseling and surveillance for at-risk relatives. Accurate diagnosis often requires non-hematopoietic germline DNA testing, which provides important biological insights into the development of different myeloid neoplasms and directs personalized patient care. Keywords: germline; predisposition; somatic; mutation; myeloid neoplasm; Down syndrome; RUNX1; CEBPA; DDX41; GATA2 1. Introduction Hematologic neoplasms are divided into myeloid and lymphoid neoplasms. Myeloid neoplasms (MNs) include myelodysplastic syndromes (MDSs), myeloproliferative neoplasms (MPNs), MDS/MPNs, and acute myeloid leukemias (AMLs), while lymphoid neoplasms encompass acute lymphoblastic leukemia (ALL) and indolent or aggressive Bor T/NK cell lymphomas. They are derived mostly from somatic mutations or cytogenetic abnormalities. A subset of neoplasms, however, result from germline mutations rather than somatic mutations. Patients carrying these mutations are more prone to develop a myeloid or lymphoid neoplasm. Importantly, germline mutations are constitutional and found in all body cells, including germ cells that can be passed on to offspring, while somatic mutations are acquired after birth and are present in cells excluding germ cells. When determining whether a mutation is germline or somatic, genetic counseling and parallel testing of patients’ familial gene profile are necessary. The development of next-generation sequencing (NGS) has aided in the discovery of these mutations and differentiation between somatic and germline mutations [1] . Historically, the terminology and nature of disease were poorly categorized until recent molecular insights.

FAQs

What does germline predisposition mean in myeloid neoplasms?

It means the cancer arises in the context of an inherited genetic alteration rather than an acquired somatic change. Germline mutations are present in constitutional DNA across body cells and can be passed to offspring.

Which conditions and gene pathways are commonly involved?

The review highlights MDS and AML within the WHO category of MNs with germline predisposition. Predisposing genes include transcription factors such as RUNX1 and CEBPA, as well as genes affecting RNA splicing and telomere biology.

Why is identifying germline mutations important for treatment?

Germline findings drive specific therapeutic strategies, particularly regarding hematopoietic stem cell transplantation (HSCT). They also require genetic counseling and ongoing surveillance for at-risk relatives.

Sep 22, 2026

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