Proteogenomic Classification of Myeloid Disorders: Integrating Molecular Profiles for Precision Medicine

Abstract

Myeloid disorders, including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPN), represent a heterogeneous group of hematologic malignancies with complex pathogenetic mechanisms. The advent of proteogenomics—an integrative approach combining proteomic and genomic data—offers a transformative pathway to refine disease classification, risk stratification, and targeted therapy selection. This review synthesizes current evidence on the proteogenomic classification of myeloid disorders, emphasizing clinical implications and emerging research directions.

Introduction

Traditional classification of myeloid malignancies has relied heavily on morphology, cytogenetics, and select molecular markers. However, heterogeneity in clinical outcomes and therapeutic response remains, even among similarly classified patients. The integration of proteomic and genomic analyses—proteogenomics—has the potential to unravel deeper mechanistic insights and define novel disease subtypes. This evolving paradigm aims to bridge the gap between genotype, phenotype, and clinical behavior, thereby facilitating precision medicine in myeloid neoplasia.

Epidemiology / Disease Burden

Myeloid disorders, encompassing AML, MDS, and MPN, collectively account for a significant proportion of adult hematologic malignancies worldwide. AML has an incidence of approximately 4 per 100,000 population annually, with higher rates observed in older adults. MDS affects up to 5 per 100,000 individuals, predominantly those over 60 years. MPNs, including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are less common but contribute substantially to morbidity due to thrombotic and hemorrhagic complications. Despite advances in therapy, overall survival remains suboptimal, underscoring the need for improved classification systems that inform prognosis and therapeutic choices.

Pathophysiology

The pathogenesis of myeloid malignancies involves a multi-step process of genetic and epigenetic alterations leading to clonal expansion and impaired hematopoietic differentiation. Genomic profiling has identified recurrent mutations in genes regulating transcription (RUNX1, CEBPA), chromatin modification (ASXL1, EZH2), splicing (SF3B1, SRSF2), and signal transduction (FLT3, JAK2). Proteomics adds a distinct dimension by elucidating post-translational modifications, protein-protein interactions, and pathway activations that cannot be inferred from DNA or RNA data alone. Proteogenomic integration allows for the identification of functionally relevant molecular aberrations, refining classification beyond traditional cytogenetic and mutational categories.

Risk Factors

Risk factors for myeloid disorders include advanced age, male sex, prior exposure to cytotoxic chemotherapy or radiation, inherited predisposition syndromes (e.g., familial platelet disorder, GATA2 deficiency), and environmental factors such as benzene exposure. Somatic mutations in genes such as DNMT3A, TET2, and ASXL1, frequently observed in clonal hematopoiesis of indeterminate potential (CHIP), significantly increase the risk for progression to overt myeloid neoplasms. Familial clustering and germline mutations are emerging as important contributors, particularly in younger patients or those with atypical presentations.

Clinical Features

Myeloid disorders present with a range of clinical manifestations dependent on the specific subtype and disease stage. AML typically manifests with symptoms of bone marrow failure, such as fatigue, infections, and bleeding. MDS can present insidiously with cytopenias, while MPNs often exhibit constitutional symptoms (e.g., weight loss, night sweats) and vascular events. Proteogenomic subtyping has revealed correlations between specific molecular signatures and clinical phenotypes, such as TP53-mutant AML associating with complex karyotypes and poor prognosis, or SF3B1 mutations predicting favorable outcomes in MDS with ring sideroblasts.

Diagnosis

Definitive diagnosis requires integration of morphological, immunophenotypic, cytogenetic, and molecular data from bone marrow and peripheral blood specimens. Next-generation sequencing (NGS) panels are now standard for detecting driver mutations. Proteomic analysis, via mass spectrometry and other high-throughput platforms, enables quantitative assessment of protein expression and modification states. Proteogenomic approaches have led to the identification of novel biomarkers, such as aberrant phosphorylation patterns and fusion proteins, that may be missed by genomics alone. This dual-layered diagnostic paradigm strengthens risk stratification and supports individualized treatment planning.

Treatment & Management

The management of myeloid disorders is tailored according to disease subtype, risk category, patient comorbidities, and molecular profile. Standard therapies include cytotoxic chemotherapy, hypomethylating agents, targeted inhibitors (e.g., FLT3, IDH1/2, JAK2), and allogeneic hematopoietic stem cell transplantation (HSCT). Proteogenomic profiling is increasingly used to identify actionable targets and predict response to specific agents. For example, the presence of FLT3-ITD mutations combined with protein phosphorylation data can inform use of FLT3 inhibitors. Proteomic markers may also predict resistance to hypomethylating agents, thus guiding early therapy escalation or clinical trial enrollment.

Recent Advances / Emerging Therapies

Recent advances in proteogenomics have facilitated the discovery of novel therapeutic targets and resistance mechanisms. Integrative studies have mapped the proteogenomic landscape of AML and MDS, revealing subgroups with distinct vulnerabilities. Combination therapies targeting both genomic mutations and dysregulated protein pathways are under investigation, such as dual inhibition of mutant IDH and BCL-2. Emerging technologies, including single-cell proteogenomics and spatial proteomics, promise to unravel intratumoral heterogeneity and microenvironmental interactions. Clinical trials are ongoing to evaluate proteogenomically-guided personalized treatment algorithms in myeloid malignancies.

Guideline Recommendations

Major hematology guidelines, including those from the World Health Organization (WHO) and European LeukemiaNet (ELN), now incorporate molecular genetics into disease classification and risk stratification. While routine proteomic testing is not yet standard, guidelines recommend comprehensive molecular profiling for all patients with newly diagnosed myeloid disorders. Expert consensus supports the integration of proteogenomic data in difficult-to-classify cases and for enrollment in precision oncology trials. The field is expected to evolve rapidly as evidence supporting the clinical utility of proteogenomics accrues.

Conclusion

Proteogenomic classification heralds a new era in the understanding and management of myeloid disorders. By integrating protein and genomic data, clinicians and researchers can refine disease taxonomy, uncover novel therapeutic targets, and personalize treatment strategies. Ongoing research and technological advancements are poised to accelerate the translation of proteogenomic insights into routine clinical practice, ultimately improving outcomes for patients with these challenging hematologic malignancies.