Myeloid Diseases Flashcards
(36 cards)
What two myeloid diseases result from proliferation without differentiation?
acute myeloid leukemia
acute lymphoblastic leukemia
What is the primary genetic defect of AML?
t (8:21 produces CBFa-ETO protein that binds to the DNA and also binds repressors instead of activators at that sight, stopping differentiation
What myeloid disease present with proliferation with differentiation?
chronic myeloid leukemia (CML)
polycythemia vera
essential thrombocythemia
primary myelofibrosis
What common pathway is responsible for the pathogenesis of several myeloid diseases with both proliferation and differentiation? (P. vera, Essential thrombo, primary myelofibroblasts)
JAK2 (JAK2 V617F) leads to uncontrolled growth and survival signals in the EPO receptor signaling pathway
What is the overarching theme of the molecular basis of myelodysplastic syndromes?
epigentic control of large groups of genes, especially by hypomethylation (causing decreased expression, TET2 is important for the demethylation of AML); this includes histone acylation and nucleosome condensation
Contrast the cellular appearance of acute and chronic myeloid disease?
acute: proliferation of undifferentiated cells
chronic: hyper cellular matrix with many mature PMNs (CML)
more eosinophils, basophils and monocytes, most are immature myeloids or appear funky
What are the clinical features of acute leukemia?
bone marrow failure: anemia, neutropenia, and thrombocytopenia
organ infiltration: bone pain, lymphadenopathy, meningeal signs, testicular swelling, skin rash, pulmonary infiltrates
What are some of the acute (emergency) presentations of CML?
Coagulopathy Acute promyelocytic leukemia – DIC picture Tumor lysis syndromes Hypercalcemia Neutropenic sepsis Leukostasis Pulmonary failure Severe pancytopenia
What are good and bad genes prognostically speaking for AML?
good: t(8;21) inv(16:16), t(15;17)
worst prognosis chromosome 5, 7; 11q23 abnl, complex
What are good and bad genes prognostically speaking for ALL?
good: t(12;21), hyper diploid
bad: t (9;22) Philly, hypdiploid, t(4;11)
What is the most characteristic way to tell AML from ALL.
if the cells have Auer rods, you know its AML, otherwise it may require CD marker staining to identify the cell line: cytogenetic results, IHC staining of biopsy or flow cytometry (uses disaggreagated tissue)
What are the treatments available for AML?
supportive treatments to stabilize blood counts, treat or prevent infections, and control metabolic problems
aggressive, high-dose, and extended chemotherapy may be curative, bone marrow transplant if disease is controlled but refractory (patient selection is key)
How does formation of Philadelphia chromosome cause proliferation.
the transaction of chromosome 9 and 22 causes the fusion of genes BCR and ABL that aren’t normally adjacent
the fusion protein that is created from this new gene leads to downstream signaling and drugs can work to bind the active site and reduce down-stream signaling
What are common clinical features of polycythemia? (broad reasons for typical symptoms (3)) as well as clinical labs.
hyper viscosity, hypervolemia and hyper metabolism; JAK2 V617F is present 95% of cases
labs: erythrocytosis with low EPO, often thrombocytosis and mild neutrophilic as well; marrow is hyper cellular with increases in all lineages
What is secondary polycythemia?
excess of RBC caused by excess secretion of EPO, due to things like conditions with chronic hypoxia, renal tumors, select neoplasms and exogenous EPO
Name common signs and symptoms of P. Vera.
headache, weakness, pruritis (aquagenic), dizziness, diaphoresis, visual disturbance, weight loss
splenomegaly, skin plethora, hepatomegaly, conjunctival plethora, systolic HTN
INCREASED risk of thrombosis causing stroke, MI etc
How is P vera treated?
phlebotomy, hydorxurea (slow bone marrow production) and aspirin to prevent thrombosis
What are the most common clinical features and lab values of essential thrombocythemia?
abnormal clotting or bleeding, erythromelagia (burning of hands and feet)
lab: high platelet count without erythrocytes or leukocytosis; JAK-2 mutations (50%), c-MPL and calreticulin gene mutations; increased large, atypical megakaryocytes
What are the genetic and secondary causes of thrombocytosis.
often JAK2, CalR, MPL are mutated iron deficiency chronic infection or inflammation malignancy connective tissue diseases post splenectomy
treatment addresses these causes by reducing thrombosis (risk factors smoking and HTN), prevent bleeding and reduce platelet count with hydroxyurea
What is myelofibrosis?
bone marrow fibrosis as the result of non clonal fibroblastic proliferation and hyperactivity induced by growth factors abnormally shed from clonal expanded megakaryocytic
(worst prognosis of MPDs)
Jack-2 mutations in 50%, calreticulin in many others
What are characteristic changes in the bone marrow and peripheral stain in myelofibrosis?
defined by fibrosis of the bone marrow and often with atypical appearing megakaryocytic
teardrop RBC
massive splenomegaly
What changes would you expect to see early in myelofibrosis vs. later?
anemia and elevated WBC/ platelets early
anemia, lower WBC/ platelets late to marrow failure and splenomegaly later
(overall, low peripheral blood counts of one or more lineages with atypical (dysplastic) morphologies, and hyper cellular marrow
What treatments are available for myelofibrosis?
ruxolitnib (JAK2 inhibitor) for consitutional symptoms and control of inflammation
hydroxyurea, palliative radiation and surgery
hematopoietic cell transplant is curative but difficult
What is the typical presentation of myelodysplastic syndrome regarding cell counts and bone marrow?
pancytopenia (anemia, thrombocytopenia, neutropenia)
and ineffective hematopoesis (hyper cellular marrow)
many evolve into AML
