Progress in Hematology: Non-Malignant, Pre-Malignant, and Malignant Disorders, and Genetically Based Therapies

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (25 July 2025) | Viewed by 2257

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Guest Editor
Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
Interests: hematopathology; molecular genetics; anatomic pathology; clinical pathology
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Special Issue Information

Dear Colleagues,

The past two decades have witnessed significant progress in the diagnosis, prognosis, and treatment of many hematologic diseases and in understanding clonal hematopoiesis, including as a potential precursor to hematologic neoplasms. The advances have often been due to an improved understanding of genetics, underlying molecular genetic pathways, and novel genetically or molecularly based therapies. Genetic evaluation, including molecular genetics, cytogenetics, or both, is integral for accurately diagnosing and determining appropriate therapies for many hematologic diseases. Novel genetically based therapies have included curative potential in acquired neoplastic diseases such as chronic myeloid leukemia and inherited non-malignant diseases such as sickle cell anemia. Novel molecular oncologic therapies include genetically targeted therapies in myeloid neoplasms and increasing genetically based applications of measurable residual disease (MRD) detection in hematologic and lymphoid neoplasms. The latter include detecting antigen receptor gene rearrangements following therapy in lymphoid neoplasms such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma, BCR::ABL1 in chronic myeloid leukemia, and MRD evaluation in acute myeloid leukemia.

Hematology includes the study of normal and abnormal hematopoiesis and non-malignant and malignant hematologic disorders, which may be inherited or acquired. Non-malignant hematologic disorders include disorders of (1) iron metabolism, (2) hemoglobin synthesis, including sickle cell anemia and thalassemia, (3) red blood cells, (4) platelets, hemostasis, and thrombosis, and (5) paroxysmal nocturnal hemoglobinuria, aplastic anemia, and (6) inherited bone marrow failure, which may progress to a hematologic neoplasm. Malignant hematologic disorders include myeloid, lymphoid, histiocytic, and dendritic cell neoplasms. These include acute and chronic leukemias, myelodysplastic syndromes, myeloproliferative neoplasms, mastocytosis, adult and pediatric lymphomas, multiple myeloma, other plasma cell neoplasms, plasmacytoid dendritic cell neoplasms, Langerhans cell neoplasms, including Langerhans cell histiocytosis, and histiocytic neoplasms, including anaplastic lymphoma kinase (ALK)+ histiocytosis and Rosai-Dorfman disease. Precursor lesions for myeloid neoplasms, including clonal hematopoiesis and clonal cytopenia of undetermined significance, and tumor-like lymphoid lesions with B-cell or T-cell predominance are also recognized by the 5th edition of the World Health Organization diagnostic classification of tumors of hematolymphoid tissues.

The second edition of our special issue in Genes welcomes research and review articles related to progress in hematology in the spectrum described above.

Dr. Rina Kansal
Guest Editor

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Keywords

  • hematology
  • hemoglobinopathies
  • erythrocyte disorders
  • platelet disorders
  • hemophilia
  • paroxysmal nocturnal hemoglobinuria
  • aplastic anemia
  • inherited bone marrow failure
  • clonal hematopoiesis
  • hematolymphoid tumors
  • leukemias
  • lymphomas
  • multiple myeloma
  • clonality
  • minimal/measurable residual disease

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Published Papers (3 papers)

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Review

14 pages, 3588 KB  
Review
Resistance Mutations in CLL: Genetic Mechanisms Shaping the Future of Targeted Therapy
by Samantha Sekeres, Erica N. Lamkin, Eduardo Bravo, Jr., Allison Cool and Justin Taylor
Genes 2025, 16(9), 1064; https://doi.org/10.3390/genes16091064 - 10 Sep 2025
Abstract
Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Western populations and remains incurable despite significant therapeutic advancements. Over the past decade, the treatment landscape has evolved from traditional chemoimmunotherapy to targeted oral agents, including Bruton’s tyrosine kinase inhibitors (BTKis) [...] Read more.
Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Western populations and remains incurable despite significant therapeutic advancements. Over the past decade, the treatment landscape has evolved from traditional chemoimmunotherapy to targeted oral agents, including Bruton’s tyrosine kinase inhibitors (BTKis) and BCL2 inhibitors (BCL2is), which have demonstrated superior efficacy and tolerability, especially in elderly patients. Venetoclax, a BCL2i, induces apoptosis in CLL cells through selective inhibition of the anti-apoptotic BCL2 protein, while BTKis, such as ibrutinib and its next-generation analogs, disrupt B-cell receptor signaling critical to CLL cell survival. However, resistance to both drug classes has emerged, including mutations in BTK and BCL2, prompting the exploration of novel therapeutic strategies. This review outlines the molecular basis and clinical implications of these resistance mechanisms, as well as emerging therapeutic solutions, including non-covalent BTKis like pirtobrutinib and BTK-targeting PROTAC degraders such as BGB-16673 and NX-2127. Additionally, we discuss promising combination therapies incorporating BTKis, BCL2is, and anti-CD20 monoclonal antibodies. Finally, we highlight the growing role of measurable residual disease (MRD) as a biomarker to guide treatment duration and evaluate therapeutic success. As resistance mechanisms continue to emerge, tailoring therapy based on underlying biology will be critical to sustaining disease control and enhancing outcomes in patients with CLL. Full article
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10 pages, 219 KB  
Review
The Impact of Genetic Polymorphisms on the Clinical Efficacy of Azole Antifungals
by Hareesh Singam and Sherif Mossad
Genes 2025, 16(9), 1058; https://doi.org/10.3390/genes16091058 - 9 Sep 2025
Abstract
Azoles are the primary agents for antifungal activity in clinical medicine due to their broad-spectrum efficacy and favorable safety profiles compared to older agents. Triazoles, including fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole, have varied pharmacokinetic and pharmacodynamic properties. This is due to various [...] Read more.
Azoles are the primary agents for antifungal activity in clinical medicine due to their broad-spectrum efficacy and favorable safety profiles compared to older agents. Triazoles, including fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole, have varied pharmacokinetic and pharmacodynamic properties. This is due to various polymorphisms in hepatic enzymes, necessitating genotype-guided dosing and therapeutic drug monitoring (TDM) to optimize treatment outcomes. This review highlights the clinical relevance of pharmacogenomics in azole therapy, particularly the role of cytochrome P450 (CYP450) enzyme polymorphisms in influencing drug levels, efficacy, and toxicity. Understanding these genetic and metabolic factors is essential for personalized antifungal treatment strategies, improving patient safety and therapeutic outcomes. Full article
30 pages, 2841 KB  
Review
Progress in the Genetics of Myelodysplastic Syndromes with a Latin American Perspective
by Ana Lisa Basquiera, Verónica Andreoli, Sofía Grille and Carolina Bárbara Belli
Genes 2025, 16(6), 687; https://doi.org/10.3390/genes16060687 - 2 Jun 2025
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Abstract
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by ineffective hematopoiesis, resulting in cytopenias, morphologic dysplasia in hematopoietic lineages, and a variable risk of progression to acute myeloid leukemia. Significant advances in the understanding of MDS have been made in [...] Read more.
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by ineffective hematopoiesis, resulting in cytopenias, morphologic dysplasia in hematopoietic lineages, and a variable risk of progression to acute myeloid leukemia. Significant advances in the understanding of MDS have been made in recent years, largely due to the implementation of molecular tools. Latin America is a highly diverse region, both ethnically and racially, and often faces resource limitations that challenge the broad applicability of recent advances in MDS. In this review, we discuss the key genes implicated in the pathogenesis and classification of MDS, and their relevance to diagnosis, prognosis, and potential therapeutic targets. We also explore the challenges associated with the identification of germline predisposition to MDS in Latin America and discuss the current availability and limitations of molecular diagnostic tools in the region. Full article
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