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52 Cards in this Set
- Front
- Back
Myeloproliferative Disorders:
Cellularity Onset (general) Hallmark finding End-result |
-Hypercellular (greater than 100%-age)
-Inc'd quantities of more than one cell lineage -Asyx onset -HALLMARK = Splenomegaly -Terminate in acute leukemia or myelofibrosis |
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JAK2 Mutation:
Which MPD is it found in? Effect (biochemically) |
Philadelphia chromosome negative MPD
V617F: phenylalanine swapped for valine |
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Polcythemia vera:
Propensity for JAK2 mutation Hetero/Homozygous |
100%; homozygous
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Myelofibrosis:
JAK2 mutation--hetero/homozygous? |
Usually paired with an additional mutation; heterozygous
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JAK2:
Ligand Effect of ligand binding Effect of mutation |
Ligand = Epo
Effect: proliferation JAK2-V617F-->constitutive autophosphorylation of JAK2 and thus constitutive proliferation: -Inhibits apoptosis -Promotes G1/S phase transition -Promotes erythroid differentiation -Promotes reticulin deposition |
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MPDs are characterized by _______. Typically, more than one _______ is _________.
Why? |
MPDs char'd by disregulated, overproduction of cells. Typically more than one cell lineage overproduced.
This is bc clonal expansion occurs at pluripotent stem cell. |
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MPD vs AML:
Cells involved Ability to differentiate |
MPD: pluripotent SCs; multiple cell lineages affected.
cells maintain ability to differentiate. AML: committed SCs; overproduciton of one cell lineage. lack of differentiation. |
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EPO Effects:
General BFU-E CFU-E |
CFU = colony forming units (early forms of RBCs); proliferate and differentiate
BFU = blast forming units; proliferation Induces globin synthesis Stimulates reticulocyte release |
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Via what mechanism is EPO released by the kidneys?
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Kidney oxygen receptors determine low O2-->signal peritubular cells-->EPO release
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Causes of decreased O2 delivery to kidneys.
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i.e., causes of EPO release
-Dec'd Hgb concentration -Dec'd atmospheric O2 -Cardiopulmonary dysfn -Left shit of O2-dissocn curve |
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How would you differentiate between a patient with erythrocytosis secondary to chronic hypoxia and a patient with polycythemia vera? Why is this possible?
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Erythrocytosis secondary to chronic hypoxia: normal to slightly elevated EPO levels, but EPO levels rise significantly if phlebotomized to nl HCTs
In PV, EPO levels remain low even when pts phlebotomized to normal HCTs bc of JAK mutations. Cells are EPO-independent. |
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In P. Vera, what is the effect of the JAK mutation on EPO levels? On normal blood cell progenitors?
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Proliferation of robotic P. Vera clones decreases EPO levels and thus inhibits proliferation of normal EPO dependent progenitors.
Clone thus has greater competitive advantage. |
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What is the diagnostic algorithm for P. Vera?
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Presence of JAK2 mutation leads to likelihood of disease
A low EPO makes P. Vera even more likely, but this is not always necessary. |
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Signs of P. Vera in erythrocytotic phase.
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Splenomegaly (sometimes)
Erythrocytosis Leukocytosis Thrombocytosis Thrombosis Hemorrhage |
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Signs of P. Vera in potpolycythemic myeloid metaplasia phase.
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Splenomegaly (common)
Anemia Leukoerythroblastosis Thrombocytopenia Systemic Syptoms BM IS FAILING |
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In 40% patients with P. vera, this is the cause of death.
Where in the body does it occur? |
Thrombosis; occurs at unusual anatomic sites! Cavernous sinuses, renal vasculature.
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In P. Vera, what does risk of thrombosis correlate with?
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HCT > 50%
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Beyond thrombosis, what are other complications of P. vera?
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Hemorrhage: due to platelet dysfn, acq'd vWF defect
Potpolycythemic Myeloid Metaplasia: ~15 years of disorder; BM failure, splenomegaly, portal HTN, fevers, sweats Acute Myeloid Leukemia: ~5% |
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What is erythromelalgia? What might it indicate?
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Erythromelalgia = burning sensation in digits, relieved by cooling
Seen in P. vera Can lead to acrocyanosis; tx w/anti-platelet tx |
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P. vera:
Therapy |
-Prevent thrombosis:
Phlebotomize Hydroxyurea Anti-platelet tx w/low dose ASA -Allogenic BM transplant (curative): Young pts HLA-matched donor |
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When is inappropriate EPO secretion seen in secondary erythrocytosis?
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Kidney tumors
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P. Vera vs Secondary Erythrocytosis:
RBC Mass Splenomegaly ALtered O2 Delivery Thrombocytosis BM Quality EPO Levels JAK2 Mutation |
P Vera:
RBC Mass inc'd Splenomegaly v. common Altered O2 delivery absent Thrombocytosis present (pluripotent HSC involvement) BM has panyhyperplasia EPO levels dec'd JAK2 Mutation PRESENT Secondary erythrocytosis: RBC Mass inc'd Splenomegaly absent Altered O2 delivery often present Thrombocytosis Absent BM has erythroid hyperplasia EPO levels inc'd JAK2 mutation ABSENT |
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Most common cause of impaired O2 transport in blood in the US. Why?
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Smoking:
CO binds to Hgb-->impaired O2 transport |
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What is spurious erythrocytosis?
Causes? |
Erythrocytosis secondary to diminished plasma volume rather than inc'd RBC mass.
Causes: Volume depletion, diuretics, stress |
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Leukoerythroblastosis:
Histologic features Indicative of? |
tear drop cells: myelofibrosis (fibers in BM) squeezes RBCs into tear drop shape
Nuc’d RBC is indicative of BM crowding Leukoerythroblastosis-->myelofibrosis |
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Utility of reticulin stain in BM.
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Detects deposition of fibers in BM in myelofibrosis.
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How does idiopathic myelofibrosis result in fibrosis?
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JAK2 mutation signals colony forming megakaryocyte units to proliferate into megak's and form Platelet-Derived GF (and platelets)
Platelet-Dertived GF stimulates fibroblasts-->collagen production; inhibition of collagenase |
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Idiopathic Myelofibrosis:
Clinical Presentation Lab presentation Radiologic findings |
Splenomegaly****** due to extramedullary hematopoiesis (IN ALL PATIENTS)
-Almost all patients are anemic (as opposed to P. Vera, where pts have erythrocytosis) -Leukocytosis, thrombocytosis common at onset, nbut pancytopenia develops as marrow fibrosis progresses -JAK2 MUTATION -Osteosclerosis on imaging |
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What is essential thrombocytosis?
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Least common myeloprolif disorer; platelet count >600,000
Major complication is thrombosis Tx = anti-platelet therapy Hydroxyurea Anegrelide |
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Essential vs Reactive Thrombocytosis:
Chronic platelet increases Thrombosis Abnormal platelet function BM fibrosis Splenomegaly Ferritin |
Essential Thrombocytosis:
Chronic platelet inc: Yes Thrombosis: Yes Abnl platelet fn: Yes BM fibrosis: Yes Splenomeg: Sometimes Ferritin:Normal Reactive thrombocytosis: Thrombosis: No Abnl platelet fn: No BM fibrosis: No Splenomeg: No Ferritin: ABNRML |
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Chronic Myelogenous Leukuemia:
Cell lines affected Defining Feature |
Expansion of all hematopoietic lineages with myeloid lineage most affected
Transformation to acute leukemia without therapy. |
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Philadelphia Chromosome:
Translocation Present in which diseases? Effects (protein formed, result) |
t(9;22)
95% of chronic myelogenous leukemia 20% of ALL 2% AML Effects: Forms hybrid BCR-ABL gene, which is a constitutively active tyrosine kinase. |
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Role of BCR.
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Unclear, but does increase oxidative burst in nphils.
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ABL and BCR are prone to have breakpoints.
What role does this play in the diseases translocations can cause? Provide 3 examples. |
ABL has one breakpoint
BCR has three breakpoints Where break occurs determines disease. P210-BCR-ABL leads to 95% of Chronic Myelogenous Leukemia P190: leads to ALL; rare CML with monocytosis P230: rare CML variant with thrombocytosis |
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BCR-ABL effects.
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Expression of B1 integrin inhibits cell adhesion
Activates mitogenic PW's: RAS, MAP kinase, Jak-Stat, P13 kinase, and Myc Shift towards anti-apoptosis Degrades inhibitory proteins CELLS CAN STILL DIFFERENTIATE |
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ABL gene:
Role |
Produces tyrosine kinase; plays role in signal transduction and regulation of cell growth
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How does the P210BCR-ABL mutation differ from normal ABL activity?
Effects of this? |
YOU GUYS, P210 BCR-ABL = PHILADELPHIA CHROMOSOME!!!!
Has much higher tyrosine kinase activity leads to proliferation signals independent of GFs Suppression of apoptosis Feedback mechs that suppress growth of normal cells allowing malignant cells to dominate |
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Why is chronic myelogenous leukemia considered chronic?
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Because without treatment, patients can survive about 5 years. As opposed to acute leukemia, where patients would live about 6 months.
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CML:
PE Findings Lab findings (General and smear findings) LAP Score |
Splenomegaly****
Fatigue (due to anemia) Weight loss Sternal tenderness Lab findings: Leukocytosis including nphils of all stages of development, myelocytes, basophilia (!!!) Thrombocytosis Anemia Leukocyte alkaline phosphae score is low (normally found in nphils; low in clones, high in inflammatory states like pnuemonia) |
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CML:
Histologic findings of peripheral smear Histologic findings of BM aspirate |
Smear:
CML Chronic PhasePeripheral Smear: Diff stages of differentiation of nphils (metamyelocytes, blasts) in periphery. ABNORMAL. Should be bands or PMNs in periphery!! BM: hypercellular (near 100%), predominance of myeloid precursors |
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When is there a risk for hypserviscosity syndrome of CML?
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WBC > 200K
Can lead to cerebrovascular, cardio ischemia, priapism. It's a perfusion problem. |
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Why does CML fail to remain in indolent chronic phase?
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Clonal evolution (to a BM failure disorder)
Myelofibrosis |
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What is clonal evolution?
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It's not BCR-ABL protein causing AML; aging DNA acquires another mutation and then can become AML. This is clonal evolution.
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CML:
Therapy |
Supportive care
Reduce number of WBCs: Leukophoresis Hydroxyurea Cytarabine |
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Interferon Alfa:
Use MOA Compare use with Hydroxyurea |
Use in CML
Note: IFNs are produced in response to antigens, such in infection or neoplasm IFN-alfa has a direct antiproliferative effect on CML progenitor cells via an unk mech Higher rate of cytogenetic response than hydroxyurea (can no longer detect Philadelphia chromosome); improvement in survival rates. |
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Why is allogeneic transplant superior to IFN-alfa in treating CML?
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80% patients with remissions after transplant have negative PCR for BCR-ABL protein. Rarely achieved w/IFN-alfa.
Transplantation involves high doses of chemotherapy followed by transplant. |
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BM Transplant Disadvantages.
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Available to limited number of pts
Considerable M&M Less effective in pts in accelerated or blast phases |
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Imatinib:
Use MOA Conerns |
Use in CML
TARGETED TX! MOA: occupies kinase pocket of BCR-ABL protein; prevents access to ATP, preventing phosphorylation of any substrate and downstream signaling. Concerns: Resistance! Especially in blastic phases. |
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What is a cytogenetic response in treating CML?
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-Undetectable BCR-ABL
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Why does resistance develop against imatinib?
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Heterogeneous mechs:
-Spontaneous mutation of tyrosine kinase binding domain -Numeric or structural cytogenetic abnlts -Overexpression of BCR-ABL |
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What is the T3151 Mutant BCR-ABL?
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Mutation making CML resistant to imatinib and second-generation treatments.
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How are patients with CML treatment resistance treated?
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Dose escalation of imatinib
2nd generation kinase inhibitors SC transplant |