Myeloproliferative disorders Flashcards
What are the two main features of stem cells?
- ability to self renew: can have symmetric division to give rise to 2 stem cells, asymmetric to give rise to Stem cell+progenitor, or asymmetric to give rise to 2 differentiated cells
- ability to differentiate into more mature cells
What does clonal hematopoietic stem cell disease mean?
-means that the cancer derives from 1 defective cell
-myeloproliferative disorders are acquired CLONAL hematopoietic stem cell disorders
-there are variable effects on differentiation of myeloid progenitors
Clonality can be shown through:
-the genetic/molecular change is found in all involved cells, e.g. JAK2 or bcd-abl
-XCIP analysis: X chromosome inactivation should be random, but in clonal disorder, the XCIP representation should be different
-surface Ab expression: antigens kappa:lambda in 2:1 ratio normally, over expression or homogeneous expression suggests clonality
What is the molecular abnormality that occurs in chronic myeloid leukemia and what is its role in the disease phenotype?
- philadelphia chromosome translocation t(9;22)–>fusion of BCR-ABL gene
- bcr-abl fusion causes increased tyrosine kinase activity (signal transduction for growth), drives overproduction of cells
- mutation is in HSC
- most common myeloproliferative disease
Describe the chronic phase of CML.
- myeloproliferative phase, mainly granulocytic
- lasts for years
- splenomegaly and leukocytosis prominent
- Hgb and platelets usually normal
- the deregulated proliferation makes it susceptible to mutations and accumulation of mutations
- most patients diagnosed in this stage
Describe the blast phase of CML.
- transformation to acute leukemia: 70% AML and 30% ALL
- lasts weeks to months, fatal if not treated
- poor response to standard AML/ALL chemo
- anemia and thrombocytopenia (lack of differentiation)
What is the therapy for CML?
-allogeneic stem cell transplant still the only cure
-non specific cytotoxic chemotherapy: Hydroxyurea, cytarabine
-Targeted therapy: Imatinib (Glivec)
blocks the signal tyrosine kinase activity of the bcd-abl fusion protein. Drug fits into ATP binding pocket and prevents ATP from binding and phosphorylating tyrosine kinase
List the myeloproliferative neoplasms.
Chronic Myeloid Leukemia (CML)
Polycythemia vera (PV)
Essential thrombocytosis (ET)
myelofibrosis (MF)
Describe features of Polycythemia vera.
- acquired clonal hematopoeitic stem cell disorder characterized by elevated red cell mass/hemoglobin
- JAK2 kinase mutation: causes up regulation of its activity in myeloid precursor cells (normal function: signal tyrosine kinase that induces growth signaling when activated by EPO or TPO)
- variable degree of leukoctosis and thrombocytosis
- EPO usually suppressed due to negative feedback
- Splenomegaly
- Hyperviscosity: blurry vision and headache, increased risk of venous thrombosis, flushed face due to congestion (and mast cell proliferation), itching after bathing (release of histamine after bathing)
- venous and arterial thrombosis is a major morbidity (increased viscosity)
What are other causes of erythrocytosis that PV must be distinguished from?
Primary causes:
-congenital EPO receptor anomalies
-PV
Secondary causes
-VHL, HIF2a, PHD mutations–>increased EPO
-2,3 DPG deficiency–>higher O2 affinity–>hypoxia
-high affinity Hg-kidney sense hypoxia–>increase EPO
-hypoxia: smoking, sleep apnea, chronic cardiac/pulm shunt, chronic lung disease, high altitude, CO poisoning
-Renal EPO over production: renal cell carcinoma, cysts, transplanted kidneys
-other EPO producing tumors: hepatocellular carcinoma, leiomyomata, cerebellar hamangioblastoma meningioma
How is polycythemia vera diagnosed?
-NEED 2 major criteria+1 minor or 1 major+2 minor
Major criteria
-Hg>18.5 in men, >16.5g/dL in women or elevated red cell mass
-Jak2 mutation
minor criteria
-bone marrow trilineage hyperplasia: increase in all three cell lines in blood
-suppressed EPO
-spontaneous EEC (red cell colony growth)
What is the clinical course of polycythemia vera?
- asympotmatic (mo-years) with increased red cell mass (hgb/Hct)
- hyperviscosity symptoms-can control with phlebotomy
- leukocytosis/thrombocytosis - increase risk of thrombosis
- progression to myelofibrosis - anemia, progressive splenomegaly-usually after 15-20 yrs
- progression to acute leukemia-usually after 20 years
Is Jak2 the cause of PV?
- leukemic cells from Jak2+ PV patients don’t harbor JAK2 mutations
- an earlier mutation may increase the chance of developing JAK2 abnormalities
- non-specific Jak2 inhibitors don’t reverse all features of jak2+ myelofibrosis
Describe the features of essential thrombocytosis.
- Chronic condition characterized by elevated platelet counts
- Must rule out secondary causes: infectious + inflammatory disorders, malignancy, iron deficiency
- Fe deficiency is the most common secondary cause of thrombocytosis
- About 50% harbor a JAK2 or cMPL mutation
- Major complication: arterial and venous thromboses
- Lower rate of transformation to myelofibrosis and/or acute leukemia (around 10%)
What does the bone marrow biopsy in essential thrombocytosis look like?
- Fluffy Megs in clusters
- normal cellular bone marrow
Describe Myelofibrosis.
- Neoplastic proliferation mature myeloid cells, particularly megakaryocytic, Megs produces PDGF→marrow fibrosis
- 30-50% harbor JAK2 mutations
- Can be Primary or a late complication of PV/ET
- Patients usually have progressive splenomegaly: due to extramedullary hematopoiesis due to fibrosed marrow
- Anemia often progressive, transfusion-dependence common
- Shortened life span (unlike ET, PV)
- Allogeneic stem cell transplant the only cure but high morbidity and mortality
- ANEMIA is defining feature to distinguish from CML
