Patients with primary myelofibrosis who carry a CALR mutation show a striking pattern when their disease progresses: the more their bone marrow architecture is remodeled, the more likely their blood cells carry additional harmful mutations. That is the central finding of a new clinicopathologic study published in Annals of Hematology, which examined 70 patients with CALR-mutated primary myelofibrosis and linked the visible state of the marrow to the molecular complexity hidden within it.
Primary myelofibrosis is a chronic blood cancer in which the bone marrow is gradually replaced by fibrous scar tissue, impairing normal blood cell production. Calreticulin, or CALR, mutations are present in roughly 20 to 30 percent of patients with this disease. Yet, as the researchers note, the relationship between marrow remodeling and molecular alterations across different disease stages in these patients had remained incompletely understood. The new study set out to fill that gap by pairing detailed microscopic examination of diagnostic bone marrow biopsies with targeted genetic sequencing.
The team conducted a cross-sectional analysis of 70 CALR-mutated primary myelofibrosis cases. Of these, 42 were classified as prefibrotic or early primary myelofibrosis and 28 as overt fibrotic disease. Within the cohort, 46 cases carried CALR type 1 mutations and 24 carried CALR type 2 mutations. Genetic analysis was performed using a 38-gene targeted next-generation sequencing panel, while marrow structure was assessed through quantitative review of diagnostic trephine biopsies, allowing the investigators to compare molecular and histologic features side by side.
One result stood out for its absence: the variant allele frequency of the CALR mutation itself did not differ significantly between prefibrotic and overt disease within either mutation subtype. In other words, the abundance of the driver mutation in the sample did not track with how advanced the marrow scarring appeared to be. What did differ was the burden of additional mutations. Overt fibrotic disease was associated with a higher prevalence of extra mutations beyond the CALR driver, seen in 18 of 28 overt cases compared with 8 of 42 early cases, a difference the authors report as statistically significant.
The pattern was even sharper for a prespecified set of adverse non-driver mutations, which were found in 13 of 28 overt cases but only 3 of 42 early cases. Mutations in two specific genes, ASXL1 and EZH2, were also more prevalent among patients with overt fibrotic disease. Both genes are known regulators of chromatin and gene expression, and their disruption has been associated with more aggressive disease behavior in myeloproliferative neoplasms.
The histologic findings mirrored this molecular gradient. Overt fibrotic primary myelofibrosis was characterized by higher reticulin grade, reflecting denser deposition of fibrous protein in the marrow. Marrow samples from these patients contained fewer megakaryocytes, the large bone marrow cells that produce platelets, and fewer tight clusters of these cells. They also had fewer large megakaryocytes, while dysplastic forms and naked nuclei, stripped of their surrounding cytoplasm, appeared more frequently. Together, these features describe a marrow that has been structurally rebuilt as fibrosis advances.
Taken together, the authors suggest that marrow remodeling is associated with adverse co-mutational complexity and may provide a tissue-level correlate of stage-related molecular alterations in patients with CALR-mutated primary myelofibrosis. In practical terms, the visible state of the biopsy could serve as a morphological signal that parallels the accumulation of unfavorable mutations, offering pathologists and hematologists a way to read molecular risk from the tissue itself.
The study’s design carries important caveats. Because the analysis was cross-sectional, it captured patients at a single point in time rather than following individuals as their disease evolved. The authors therefore emphasize that longitudinal studies and comparative cohorts including patients with other driver mutations are required to validate these findings and determine their broader applicability. Until such studies are completed, the association between marrow architecture and mutation burden in CALR-mutated disease stands as an observational link rather than a proven causal sequence.
Even so, the work adds a meaningful layer to the understanding of primary myelofibrosis, a disease whose clinical course varies widely between patients. By showing that the degree of fibrosis and the loss of normal megakaryocyte structure coincide with a heavier load of adverse mutations, the study offers a framework for integrating what the pathologist sees under the microscope with what the sequencer detects in the DNA. For the substantial minority of patients whose myelofibrosis is driven by CALR, that integration may eventually help refine how disease stage and molecular risk are assessed together.
Subject of Research: The association between bone marrow remodeling and additional adverse mutations across disease stages in CALR-mutated primary myelofibrosis.
Article Title: Marrow remodeling is associated with adverse co-mutational complexity in CALR-mutated primary myelofibrosis: a clinicopathologic study
Article References: Pan, Y., Wang, X., Wen, S., Liu, X., Wang, Z., Cheng, Z., Luo, J., & Yang, L. (2026). Marrow remodeling is associated with adverse co-mutational complexity in CALR-mutated primary myelofibrosis: a clinicopathologic study. Annals of Hematology. https://doi.org/10.1007/s00277-026-07342-0
Image Credits: AI Generated
DOI: 10.1007/s00277-026-07342-0
Keywords: primary myelofibrosis, CALR mutation, bone marrow fibrosis, ASXL1, EZH2, megakaryocytes, reticulin, next-generation sequencing, myeloproliferative neoplasms, trephine biopsy, variant allele frequency, disease progression
News Source: Ophelia Keating. (November 8, 2026). Bone Marrow Changes Track With Extra Mutations in CALR-Mutated Myelofibrosis. Scienmag.
