myeloproliferative neoplasms

Question 1

• are clonal hematopoietic disorders caused by genetic mutations in the hematopoietic stem cells (HSCs) that result in expansion, excessive production, and accumulation of mature erythrocytes, granulocytes, platelets, and mast cells
• Each has a chronic course that may terminate as acute leukemia, myelofibrosis, or a coagulopathy

Answer 1

myeloproliferative neoplasms (MPN)

Question 2

MPN

• Molecular analysis is now incorporated into the diagnosis workup of MPNs, research molecular advances were capped by the discovery of the (?); this discovery allowed for refinement of the classification of MPNs
• Myeloproliferation largely is due to hypersensitivity or independence of normal (?) regulation resulting from genetic mutations that reduces cytokine levels through negative feedback systems normally induced by mature cells
• All of the MPNs involve dysregulation at the multipotent hematopoietic stem cell (?)

Answer 2

• JAK2, Janus kinase 2 (JAK2V617F mutation)
• cytokine
• CD34

Question 3

• an MPN arising from a single genetic translocation in a pluripotential HSC producing a clonal overproduction of the myeloid cell line
• occurs at all ages but is seen predominantly in those aged 46 to 53 years; it represents about 20% of all cases of leukemia, is slightly more common in men than in women
• begins with a chronic clinical phase and, if untreated, progresses to an accelerated phase in 3 to 4 years and often terminates as an acute leukemia (blast crisis phase)

Answer 3

chronic myeloid leukemia (CML)

Question 4

• Presence of the BCR-ABL1 gene (Philadelphia chromosome/Ph’)
• Reciprocal translocation between the long arms (q arm) of chromosomes 9 and 22 → t(9;22)
• This acquired somatic mutation specifically reflects the translocation of an ABL1 proto-oncogene from band q34 of chromosome 9 to the breakpoint cluster region (BCR) of band q11 of chromosome 22 (q34;q11)
• Also found in FAB M1(3-5%)and FAB L1 and L2 (10-25%

Answer 4

chronic myeloid leukemia (CML)

Question 5

CML

has constitutive kinase activity that deregulates signal transduction pathways, causing abnormal cell cycling, inhibition of apoptosis, and increased proliferation of cells

Answer 5

BCR-ABL protein

Question 6

CML phase

• Most cases (85%) are diagnosed in this phase
• Frequent infection, anemia secondary to massive massive pathologic accumulation of myeloid progenitor cells in bone marrow, peripheral blood, and extramedullary tissues
• NEUTROPHILIA WITH ALL MATURATIONAL STAGES PRESENT, BASOPHILIA, EOSINOPHILIA
• Progressive fatigue and malaise, low-grade fever, anorexia, weight loss, and bone pain
• Night sweats and fever, associated with an increased metabolism caused by granulocytic cell turnover, may occur
• Splenomegaly; splenic infarction is common because of the abnormal overproduction and accumulation of granulocyte precursors in the bone marrow, spleen, and blood
• On fresh incision, extramyeloid masses appear green (Chloromas), presumably because of the presence of the myeloid enzyme myeloperoxidase

Answer 6

chronic phase

Question 7

CML phase

• Increased splenomegaly
• Worsening anemia and thrombocytopenia
• Gradual failure of response to treatment
• Additional cytogenetic abnormalities
• 10-19%blasts

Answer 7

accelerated phase

Question 8

CML phase

• involves the peripheral blood, bone marrow, and extramedullary tissues
• Based on AL definitions, blasts constitute more than 20% of total BM cellularity, and the peripheral blood exhibits increased blasts
• Extramedullary growth may occur as lymphocytic or myeloid cell proliferations; the latter are often referred to as granulocytic sarcoma
• Clinical symptoms of blast crisis mimic those of AL, including severe anemia, leukopenia of all WBCs except blasts, and thrombocytopenia

Answer 8

blast crisis (acute)

Question 9

CML findings

BLOOD:
* Marked expansion of the (?)
* Anemia and thrombocytopenia (variable)
* (?) shift with few blasts in the peripheral blood
* Extramedullary hematopoiesis (spleen, liver)

BONEMARROW:
* Intense (?)
* (?) are increased in approximately 20% of patients
* Increased (?) density is associated with an increase in myelofibrosis
* Presence of (?)

Answer 9

• granulocyte pool
• left
• hypercellularity
• reticulin fibers
• megakaryocyte
• pseudo-gaucher cells

Question 10

used to differentiate CML from leukemoid reaction

Answer 10

LAP

Question 11

• a clonal stem cell proliferation affecting primarily the erythroid series, characterized by excessive proliferation of erythroid and also usually granulocytic and megakaryocytic elements in the marrow
• The very slow evolution of the malignant erythroid clone leads to overexpansion of the red cell mass, hypervolemia, and splenomegalic red cell pooling
• These consequences eventually cause generalized marrow hyperplasia with subsequent increases in the quantity of all three cell lines
• Associated with the JAK2 mutation, JAK2 V617F, is detected in more than 95% of patients and is found on chromosome band 9p24 ; also associated with JAK2 exon 12 mutation

Answer 11

polycythemia vera (PV)

Question 12

• Tyrosine kinase phosphorylates signal transducers and activators of transcription (STAT) proteins, eventually generating transcription proteins that bind promotor regions and signal gene expression
• Controls transphosphorylation through conformational inhibition
• Constitutive tyrosine kinase activity of the mutated JAK2 protein causes continuous activation of several signal transduction pathways that are normally activated after erythropoietin stimulation via the erythropoietic receptor
• Mutated JAK2 is active and will phosphorylate STAT proteins in the absence of erythropoietin or will overphosphorylate in its presence

Answer 12

JAK 2 protein

Question 13

PV

• Increased Hct: increase BM production
• Types: Primary, secondary with appropriate EPO production, inappropriate production of EPO

Answer 13

absolute PV

Question 14

PV

• Increase hematocrit; decrease plasma volume
• Dehydration, stress, spurious polycythemia, anxiety
• Gaisbock’s syndrome: spurious polycythemia

Answer 14

relative PV

Question 15

• PV often presents with a history of mild symptoms occurring for several years
• Increased RCM produces blood (?), often resulting in cardiovascular disease
• In the early stages of the disease, before treatment, extended periods of (?) (60%) and hyperviscosity produce (?) in about 50% of patients with PV
• Hyperviscosity and hyperproliferation and include headache, weakness, pruritis, weight loss, and fatigue
• About half of patients have thrombocytosis and 1/3 experience thrombotic or hemorrhagic episodes
• patients older than 60 years of age or those associated with a history of thrombosis are considered high risk for thrombotic or hemorrhagic events

Answer 15

• hyperviscosity
• high HCT
• hypertension
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