What is myeloproliferative neoplasm (MPN)?

What is Myeloproliferative Neoplasm (MPN)?

Myeloproliferative neoplasms are clonal hematopoietic stem cell disorders characterized by excessive proliferation of one or more differentiated myeloid cell lineages (red blood cells, white blood cells, or platelets) in the bone marrow, arising from acquired genetic driver mutations that activate the JAK-STAT signaling pathway. 1

Core Disease Characteristics

Biological Basis

• MPNs originate from acquired mutations in hematopoietic stem cells that cause uncontrolled production of mature, functional blood cells without the normal requirement for cytokine stimulation 2, 3
• The excessive cell production and abnormal signaling from driver mutations cause chronic inflammation and significantly increase the risk of thrombotic complications and vascular events 2
• These disorders represent true malignancies with potential for transformation to acute myeloid leukemia, which carries a poor prognosis 1, 3

Major Disease Subtypes

The WHO classification recognizes four main categories of MPNs 4:

Philadelphia chromosome-negative classical MPNs:

• Polycythemia vera (PV): characterized by excessive red blood cell production, with estimated U.S. prevalence of 148,000 patients 1
• Essential thrombocythemia (ET): characterized by excessive platelet production, with estimated U.S. prevalence of 134,000 patients 1
• Primary myelofibrosis (PMF): characterized by bone marrow fibrosis and extramedullary hematopoiesis, with estimated U.S. prevalence of 13,000 patients 1

Philadelphia chromosome-positive MPN:

• Chronic myeloid leukemia (CML): defined by the BCR-ABL1 fusion gene resulting from the Philadelphia chromosome translocation 1, 3

Non-classical Philadelphia-negative MPNs:

• Chronic neutrophilic leukemia and chronic eosinophilic leukemia 4

Myeloproliferative neoplasms, unclassifiable (MPN-U):

• Cases not fulfilling diagnostic criteria for any specific entity, including early-phase MPNs, advanced fibrotic MPNs, and cases obscured by inflammatory or neoplastic disorders 4

Molecular Pathogenesis

Driver Mutations

The discovery of JAK2 V617F mutation in 2005 revolutionized MPN diagnosis and understanding 3. The key driver mutations that activate JAK-STAT signaling include:

• JAK2 V617F: found in the majority of PV, ET, and PMF cases, though only 22-26% of pediatric cases 5, 3
• JAK2 exon 12 mutations: found in JAK2 V617F-negative PV cases 5, 3
• CALR (calreticulin) mutations: associated with improved survival compared to JAK2-mutated and triple-negative PMF, and lower thrombosis risk 1, 3
• MPL (myeloproliferative leukemia virus oncogene) mutations: associated with intermediate prognosis and higher thrombosis risk 1, 3

These driver mutations are largely mutually exclusive 3.

Additional Prognostic Mutations

Coexisting mutations in chromatin modifiers, spliceosome components, DNA methylation modifiers, and tumor suppressors drive disease progression and leukemic transformation 6:

• ASXL1: independently associated with inferior overall survival and leukemia-free survival 1
• EZH2: independently associated with inferior overall survival 1
• IDH1/2: independently associated with inferior outcomes 1
• SF3B1, TET2, SRSF2, TP53: provide additional prognostic information 5, 6

Clinical Manifestations and Complications

Symptom Profile

MPNs present with a complicated and variable symptom profile that includes 1:

• Constitutional symptoms (fatigue, night sweats, weight loss)
• Pruritus (particularly aquagenic pruritus in PV)
• Symptomatic splenomegaly
• Laboratory abnormalities: erythrocytosis, thrombocytosis, leukocytosis

Major Complications

PV and ET are characterized by significant thrombohemorrhagic complications 1:

• Arterial thrombotic events occur in approximately 3.8% of surgical cases 7
• Major hemorrhage complicates approximately 10.5% of surgeries in ET patients despite optimal management 7
• High risk of transformation to myelofibrosis and acute myeloid leukemia 1

Patients with MPN have substantially inferior survival compared to matched controls, with myelofibrosis patients having the worst outcomes 1.

Diagnostic Approach

Essential First Step

FISH or RT-PCR for BCR-ABL1 is mandatory to exclude CML, as this fundamentally changes diagnosis and management 1, 5. If BCR-ABL1 is positive, the patient has CML and requires tyrosine kinase inhibitor therapy rather than MPN-directed treatment 1.

Core Diagnostic Workup

The NCCN recommends the following essential studies 1, 5:

Laboratory studies:

• Complete blood count with differential to assess for erythrocytosis, thrombocytosis, leukocytosis 1, 5
• Peripheral blood smear examination 1, 5
• Comprehensive metabolic panel with uric acid, LDH, and liver function tests 1, 5
• Serum erythropoietin level (particularly for suspected PV, where levels are typically low despite erythrocytosis) 5

Molecular testing:

• JAK2 V617F mutation testing as the initial molecular test 1, 5
• If JAK2 V617F negative, test for CALR and MPL mutations 1, 5
• Comprehensive myeloid mutation panel for prognostic information 5

Bone marrow evaluation:

• Bone marrow aspirate and biopsy with trichrome and reticulin staining 1, 5
• Bone marrow cytogenetics (karyotype ± FISH) 1, 5

WHO Diagnostic Criteria Examples

For Essential Thrombocythemia, diagnosis requires all 4 major criteria OR the first 3 major criteria plus the minor criterion 1:

Major criteria:

1. Platelet count ≥450 × 10⁹/L
2. Bone marrow biopsy showing megakaryocyte proliferation with enlarged, mature, hyperlobulated megakaryocytes without significant granulocytic or erythroid proliferation
3. Not meeting WHO criteria for other myeloid neoplasms
4. Presence of JAK2, CALR, or MPL mutation

Minor criterion:

• Presence of clonal marker or absence of reactive thrombocytosis

Clinical Significance

MPNs represent a spectrum from chronic, manageable conditions to life-threatening malignancies 1. The identification of driver mutations has transformed diagnosis and enabled targeted therapies, particularly JAK inhibitors for myelofibrosis 1, 3. However, these remain incurable diseases outside of allogeneic stem cell transplantation, with ongoing risks of thrombosis, bleeding, and leukemic transformation that require lifelong monitoring and management 1.