Myeloproliferative disorders Flashcards Preview

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Flashcards in Myeloproliferative disorders Deck (17):
1

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

2

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

3

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

4

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

5

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)

6

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

7

List the myeloproliferative neoplasms.

Chronic Myeloid Leukemia (CML)
Polycythemia vera (PV)
Essential thrombocytosis (ET)
myelofibrosis (MF)

8

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)

9

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

10

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)

11

What is the clinical course of polycythemia vera?

1. asympotmatic (mo-years) with increased red cell mass (hgb/Hct)
2. hyperviscosity symptoms-can control with phlebotomy
3. leukocytosis/thrombocytosis - increase risk of thrombosis
4. progression to myelofibrosis - anemia, progressive splenomegaly-usually after 15-20 yrs
5. progression to acute leukemia-usually after 20 years

12

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

13

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%)

14

What does the bone marrow biopsy in essential thrombocytosis look like?

-Fluffy Megs in clusters
-normal cellular bone marrow

15

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

16

What does the peripheral blood smear of myelofibrosis look like?

-tear drop RBCs
-nucleated RBCs
-early myeloid cells

17

What laboratory tests should be done to distinguish between ET, PV, MF?

-CBC:
PV: high Hb, high platelets
ET: normal hb, high platelets
-blood smear: can tell myelofibrosis
-EPO level (low in PV)
-JAK2 mutation
-ESR/CRP (acute phase reactants, to distinguish from inflammation)