Hematopoietic and lymphocytic neoplasms (HLNs) are a diverse group of malignancies affecting blood and lymphatic systems, with outcomes varying from manageable conditions to fatal diseases. Traditional classifications rely on morphology, karyotyping, and fluorescence in situ hybridization (FISH). However, recent advancements in next-generation sequencing (NGS) allow simultaneous genetic profiling of multiple genes, enhancing diagnostic precision and therapeutic strategies. This review examines key molecular applications in diagnosing and managing HLNs, addressing current challenges and proposing solutions to optimize clinical utility.
Chronic Myeloid Leukemia (CML)
CML, historically identified by leukocytosis, is characterized by the BCR::ABL1 fusion gene resulting from the Philadelphia chromosome translocation. This oncogenic fusion drives aberrant tyrosine kinase activity, promoting unchecked proliferation. The introduction of imatinib, a targeted tyrosine kinase inhibitor (TKI), revolutionized CML treatment, leading to normalized white blood cell (WBC) counts within months. However, resistance mutations necessitate molecular monitoring via quantitative PCR, FISH, and karyotyping, ensuring optimal therapeutic adjustments.
Molecular Applications in BCR::ABL1-Negative Myeloid Neoplasms
Certain myeloid neoplasms, such as chronic neutrophilic leukemia (CNL) and chronic eosinophilic leukemia (CEL), lack the BCR::ABL1 fusion gene but exhibit distinct genetic markers like CSF3R mutations in CNL. Classical myeloproliferative neoplasms (MPNs) include polycythemia vera, essential thrombocythemia, and primary myelofibrosis, driven by JAK2, MPL, or CALR mutations. The application of NGS enables comprehensive mutational profiling, aiding accurate diagnosis and prognostication.
Genetic Abnormalities in Myeloid/Lymphoid Neoplasms with Eosinophilia and Tyrosine Kinase Fusion Genes
This newly classified subgroup within the WHO-HAEM5 includes cases with eosinophilia driven by tyrosine kinase fusion genes like PDGFRA, PDGFRB, and FGFR1. Rapid molecular diagnostics are crucial, as imatinib-sensitive fusions lead to favorable outcomes. FISH and targeted sequencing facilitate precise identification and treatment selection.
Genetic Abnormalities in Myelodysplastic Syndromes (MDS) and MDS/MPN
MDS is defined by cytopenia, morphological dysplasia, and potential progression to acute myeloid leukemia (AML). Genetic abnormalities, including deletions (5q-, 7q-, 20q-) and mutations in splicing genes (SF3B1, SRSF2), epigenetic regulators (ASXL1, TET2), and tumor suppressors (TP53), guide prognosis and therapeutic strategies. In MDS/MPN, mutations in genes such as ETNK1 and SETBP1 further refine diagnostic and risk stratification approaches.
Genetic Abnormalities in AML and Diagnostic Approaches
AML is a highly heterogeneous disease with approximately 50% of cases displaying chromosomal abnormalities. Favorable mutations include PML::RARA and RUNX1::RUNX1T1, while adverse mutations involve TP53, FLT3, and KMT2A rearrangements. The use of cytogenetics, FISH, and NGS panels aids in classification, prognostication, and treatment selection. The advent of targeted therapies against FLT3 and IDH1/2 mutations underscores the clinical impact of molecular profiling.
Genetic Abnormalities in B- and T-Cell Lymphoproliferative Disorders (LPDs) and Lymphomas
Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) CLL/SLL prognosis is closely linked to IGVH mutational status, with hypermutated IGVH correlating with better outcomes. Cytogenetic abnormalities, such as deletions (13q-, 11q-, 17p-), and mutations in TP53 and NOTCH1 influence therapeutic strategies. The introduction of Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib, has transformed management, though resistance mutations (BTK C481S) necessitate molecular monitoring.
Low- and High-Grade B-Cell Lymphomas Low-grade lymphomas, including follicular lymphoma and mantle cell lymphoma, frequently harbor BCL2, BCL6, or CCND1 translocations. Burkitt lymphoma is driven by MYC rearrangements, confirmed via FISH. In high-grade B-cell lymphomas, concurrent MYC and BCL2/BCL6 rearrangements define "double-hit" lymphomas, which require aggressive treatment. Emerging mutational profiling stratifies diffuse large B-cell lymphoma (DLBCL) into prognostic subtypes.
T-Cell Lymphomas T-cell lymphomas exhibit diverse genetic aberrations, with ALK rearrangements defining anaplastic large cell lymphoma. Mutations in RHOA, IDH2, and STAT3/5B influence peripheral T-cell lymphoma and large granular lymphocytic leukemia classification. Clonal T-cell receptor (TCR) gene rearrangement detection remains pivotal in distinguishing reactive and neoplastic processes.
Conclusions
Molecular genetic testing has revolutionized the diagnosis and management of hematopoietic and lymphocytic neoplasms. High-throughput sequencing technologies, coupled with bioinformatics advancements, enhance disease classification, risk stratification, and personalized treatment selection. Ongoing research aims to refine molecular assays and develop novel targeted therapies, ultimately improving patient outcomes.
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The study was recently published in the Journal of Clinical and Translational Pathology .
Journal of Clinical and Translational Pathology (JCTP) is the official scientific journal of the Chinese American Pathologists Association (CAPA). It publishes high quality peer-reviewed original research, reviews, perspectives, commentaries, and letters that are pertinent to clinical and translational pathology, including but not limited to anatomic pathology and clinical pathology. Basic scientific research on pathogenesis of diseases as well as application of pathology-related diagnostic techniques or methodologies also fit the scope of the JCTP.
