What causes bone marrow fibrosis in primary myelofibrosis (Primary Myelofibrosis, PM)?

Bone Marrow Fibrosis in Primary Myelofibrosis: Pathophysiology

The bone marrow fibrosis observed in primary myelofibrosis (PM) is due to increased release of fibroblastic growth factors such as platelet-derived growth factor (PDGF). This is the correct answer (option D) based on current understanding of the pathophysiology of myelofibrosis.

Pathogenesis of Bone Marrow Fibrosis in PMF

Primary myelofibrosis is characterized by a stem cell-derived clonal myeloproliferation that leads to bone marrow fibrosis through several mechanisms:

1. Cytokine-Mediated Fibrosis:

   • The fibrosis is not caused by malignant proliferation of fibroblasts (ruling out option A)
   • Instead, normal bone marrow fibroblasts are stimulated by cytokines and growth factors released from the neoplastic hematopoietic clone 1
   • These growth factors include PDGF, transforming growth factor-beta (TGF-β), and other inflammatory cytokines 2

2. Megakaryocyte Involvement:

   • Abnormal megakaryocytes play a central role in the pathogenesis
   • PMF is characterized by megakaryocytes that are often found in sizable clusters with aberrant nuclear/cytoplasmic ratio and hyperchromatic, bulbous, or irregularly folded nuclei 1
   • These atypical megakaryocytes release excessive amounts of fibrogenic cytokines 2

3. Reactive Process, Not Primary Fibroblast Abnormality:

   • The fibrosis is a reactive process to the abnormal hematopoietic clone
   • It is not due to decreased apoptosis of normal fibroblasts (ruling out option C)
   • It is not caused by increased erythropoietin stimulating fibroblast proliferation (ruling out option B) 1, 2

Diagnostic Implications

The WHO diagnostic criteria for PMF emphasize the importance of bone marrow morphology:

• Major Criteria for PMF Diagnosis:

  1. Presence of megakaryocyte proliferation and atypia, usually accompanied by reticulin and/or collagen fibrosis
  2. Not meeting WHO criteria for other myeloid neoplasms
  3. Demonstration of JAK2, CALR, or MPL mutation, or in absence of these, no evidence of bone marrow fibrosis due to other causes 1

• Bone Marrow Examination:

  • Reveals increased megakaryocyte growth with conspicuous abnormalities
  • Shows granulocyte proliferation
  • Demonstrates reticulin and/or collagen fibrosis (though not required in prefibrotic phase) 1

Clinical Significance of Fibrosis

The degree of bone marrow fibrosis has important prognostic implications:

• Bone marrow fibrosis is an adverse prognostic variable in myeloproliferative neoplasms 2
• The 2016 WHO classification distinguishes "prefibrotic" from "overtly fibrotic" PMF, as this distinction has prognostic relevance 3
• The fibrosis contributes to an impaired microenvironment that favors malignant over normal hematopoiesis 2

Treatment Considerations

Current treatment approaches for PMF have varying effects on bone marrow fibrosis:

• JAK2 Inhibitors (ruxolitinib, fedratinib, pacritinib):

  • Primarily palliative, targeting symptoms, splenomegaly, and constitutional symptoms
  • Limited effect on the underlying fibrosis 3, 2

• Allogeneic Hematopoietic Stem Cell Transplantation:

  • Currently the only curative approach
  • Reliably results in resolution of bone marrow fibrosis in patients with myelofibrosis 2

• Novel Approaches:

  • Targeting the clonal hematopoietic stem/progenitor cells
  • Inhibiting aberrant signaling pathways
  • Blocking fibrogenic cytokines
  • Modifying the tumor microenvironment 2

Understanding that the bone marrow fibrosis in PMF is driven by increased release of fibroblastic growth factors from the abnormal clone, rather than by primary fibroblast abnormalities, is crucial for developing targeted therapeutic strategies that might modify the natural history of this disease.