Genomic insights transform diagnosis, prognosis, and therapy in BCR::ABL1-negative myeloproliferative neoplasms.

bcr:ABL1-negative myeloproliferative neoplasms (Ph-negative MPNs) are clonal hematologic malignancies characterized by aberrant myeloid proliferation driven by canonical driver mutations in JAK2, MPL, or CALR. The identification of these driver lesions has transformed diagnosis and therapeutic development; however, disease phenotype, clinical behavior, and treatment response are further shaped by cooperating mutations, clonal architecture, and the order of mutation acquisition. In parallel with these genetic insights, transcriptional and cellular readouts reflecting disease-state activity are increasingly recognized as critical complements to genotype-based classification. In this context, platelet-derived CREB3L1 mRNA expression has emerged as a lineage-associated biomarker that distinguishes neoplastic from reactive blood cell increases and reflects tumor-intrinsic proliferative states. Recent therapeutic advances increasingly aim to move beyond pathway-level cytoreduction toward disease modification and clonal control, including interferon-based strategies, mutation-selective approaches targeting oncogenic JAK2 or mutant CALR, and allele-directed therapeutic concepts currently under clinical and preclinical development. This review synthesizes recent advances in the genetic architecture, clonal evolution, and therapeutic targeting of Ph-negative MPNs, with particular emphasis on integrating mutational profiling and functional biomarkers to refine diagnosis, guide disease-modifying therapies, and enable mechanism-aligned molecular monitoring.