Myeloid Neoplasms
MPNs & MDS — from a single broken JAK/STAT switch to WHO classification and management.
Deconstructing “myeloproliferative neoplasm”
The term itself is the definition. Three words, three ideas.
Myelo-
Myeloid lineage — the non-lymphoid cells: red cells, platelets, neutrophils, eosinophils, basophils.
-proliferative
Increased numbers — a -cytosis, -cythemia, or -philia.
Neoplasm
A clonal mutation driving autonomous growth. Not reactive, not secondary.
Normal signalling vs a stuck JAK2
Normally a growth factor must bind before JAK phosphorylates and STAT carries the signal to the nucleus — supply meets demand. In an MPN, mutant JAK2 fires with no ligand at all. Toggle the switch.
The result: unregulated, growth-factor-independent, clonal production of blood cells.
Sorted by the Philadelphia chromosome
BCR-ABL
JAK2 95%
JAK2 / CALR / MPL
JAK2 / CALR / MPL
Reactive vs clonal
Most high counts are a normal response to stress — not cancer. The clinical art is separating the two.
Reactive (secondary)
- Infection, inflammation
- Tissue necrosis
- Stress / hypoxia, smoking
- Medications
Clonal (primary)
- Myeloproliferative neoplasm — a driver mutation
- Autonomous, growth-factor independent
A neutrophil count > 50 ×10⁹/L usually points away from a purely reactive cause.
High hemoglobin: read the EPO
Hb 18.4, Hct 54%. One test forks the diagnosis — erythropoietin.
lung disease · altitude · renal tumor
test JAK2
EPO 1.6 mIU/mL (low) + JAK2 V617F detected = polycythemia vera.
Neutrophilia & thrombocytosis
Chronic myeloid leukemia
- Palpable splenomegaly (50–90%)
- Insidious fatigue, weight loss
- Hyperleukocytosis tolerated — mature, small cells
- Phases: chronic → accelerated → blast
Essential thrombocythemia
Persistent high platelets, JAK2 negative → look for CALR.
Patient tested CALR positive — confirming clonality in a Ph-negative MPN.
Clinical features & complications
CNS
Headache, dizziness, visual disturbance.
Budd–Chiari
Hepatic-vein thrombosis — a red flag for MPN.
Erythromelalgia
Burning pain; gout.
Thrombosis
Stroke, MI, DVT — ~20% risk.
Transformation
Progression to fibrosis or acute leukemia (blast phase).
MDS: ineffective proliferation
MPN and MDS are mirror images. Both are clonal — but one makes too many cells, the other makes too few despite trying.
MPN · effective
Mutation + clonal cytosis (high counts) = effective proliferation.
MDS · ineffective
Mutation + clonal cytopenia (low counts) = ineffective proliferation (dysplasia).
- Acquired somatic mutations in stem cells
- Dysplasia — abnormal maturation
- Disease of aging
Macrocytic anemia that won’t respond
| Hb | 7.4 g/dL |
| MCV | 119.9 fL |
| B12 trial | Failed — rules out nutritional cause |
| Marrow | Hypercellular but ineffective |
Smear findings
- Anisopoikilocytosis
- Hypogranulated neutrophils (“washed-out”)
- Basophilic stippling
Managing MPNs
Prevention
Aspirin — reduce vascular events.
Thrombosis
Systemic anticoagulation.
Cytoreduction
Hydroxyurea, interferon; venesection for PV.
Targeted
JAK2 inhibitor (ruxolitinib); TKI (imatinib) for CML.
Four things to carry
Context
Most high counts are reactive, not cancer.
Definition
MPNs are clonal, autonomous, growth-factor independent.
Genetics
JAK2, CALR, MPL are the diagnostic keys for classical MPNs.
MDS
Clonal but ineffective — dysplasia + cytopenia.
“Prevent the thrombosis; watch for fibrosis and leukemic transformation.”
End of lecture.
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