Myeloid Diseases

Question 1

What two myeloid diseases result from proliferation without differentiation?

Answer 1

acute myeloid leukemia

acute lymphoblastic leukemia

Question 2

What is the primary genetic defect of AML?

Answer 2

t (8:21 produces CBFa-ETO protein that binds to the DNA and also binds repressors instead of activators at that sight, stopping differentiation

Question 3

What myeloid disease present with proliferation with differentiation?

Answer 3

chronic myeloid leukemia (CML)
polycythemia vera
essential thrombocythemia
primary myelofibrosis

Question 4

What common pathway is responsible for the pathogenesis of several myeloid diseases with both proliferation and differentiation? (P. vera, Essential thrombo, primary myelofibroblasts)

Answer 4

JAK2 (JAK2 V617F) leads to uncontrolled growth and survival signals in the EPO receptor signaling pathway

Question 5

What is the overarching theme of the molecular basis of myelodysplastic syndromes?

Answer 5

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

Question 6

Contrast the cellular appearance of acute and chronic myeloid disease?

Answer 6

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

Question 7

What are the clinical features of acute leukemia?

Answer 7

bone marrow failure: anemia, neutropenia, and thrombocytopenia
organ infiltration: bone pain, lymphadenopathy, meningeal signs, testicular swelling, skin rash, pulmonary infiltrates

Question 8

What are some of the acute (emergency) presentations of CML?

Answer 8

Coagulopathy 
Acute promyelocytic leukemia – DIC picture
Tumor lysis syndromes
Hypercalcemia
Neutropenic sepsis
Leukostasis
Pulmonary failure
Severe pancytopenia

Question 9

What are good and bad genes prognostically speaking for AML?

Answer 9

good: t(8;21) inv(16:16), t(15;17)

worst prognosis chromosome 5, 7; 11q23 abnl, complex

Question 10

What are good and bad genes prognostically speaking for ALL?

Answer 10

good: t(12;21), hyper diploid
bad: t (9;22) Philly, hypdiploid, t(4;11)

Question 11

What is the most characteristic way to tell AML from ALL.

Answer 11

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)

Question 12

What are the treatments available for AML?

Answer 12

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)

Question 13

How does formation of Philadelphia chromosome cause proliferation.

Answer 13

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

Question 14

What are common clinical features of polycythemia? (broad reasons for typical symptoms (3)) as well as clinical labs.

Answer 14

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

Question 15

What is secondary polycythemia?

Answer 15

excess of RBC caused by excess secretion of EPO, due to things like conditions with chronic hypoxia, renal tumors, select neoplasms and exogenous EPO

Question 16

Name common signs and symptoms of P. Vera.

Answer 16

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

Question 17

How is P vera treated?

Answer 17

phlebotomy, hydorxurea (slow bone marrow production) and aspirin to prevent thrombosis

Question 18

What are the most common clinical features and lab values of essential thrombocythemia?

Answer 18

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

Question 19

What are the genetic and secondary causes of thrombocytosis.

Answer 19

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

Question 20

What is myelofibrosis?

Answer 20

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

Question 21

What are characteristic changes in the bone marrow and peripheral stain in myelofibrosis?

Answer 21

defined by fibrosis of the bone marrow and often with atypical appearing megakaryocytic
teardrop RBC
massive splenomegaly

Question 22

What changes would you expect to see early in myelofibrosis vs. later?

Answer 22

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

Question 23

What treatments are available for myelofibrosis?

Answer 23

ruxolitnib (JAK2 inhibitor) for consitutional symptoms and control of inflammation
hydroxyurea, palliative radiation and surgery
hematopoietic cell transplant is curative but difficult

Question 24

What is the typical presentation of myelodysplastic syndrome regarding cell counts and bone marrow?

Answer 24

pancytopenia (anemia, thrombocytopenia, neutropenia)
and ineffective hematopoesis (hyper cellular marrow)

many evolve into AML

Question 25

What are characteristic cellular features of myelodysplastic syndrome?

Answer 25

ineffectively maturing

pseudo pelger-huet cell (bi lobed PMN)
ring sideroblasts with prussian blue stain (deposition of iron around the nucleus)
“dyserythropoeisis”
micromegakaryocyte
hyper cellular and architecturally disorganized marrow

Question 26

What is special about MDS myelodysplatic syndrome associated with isolated del (5q)?

Answer 26

it is drug responsive: lenalidomide

Question 27

Name three ways to gauge MDS prognosis.

Answer 27

proportion of blasts in the marrow (higher precent is worse)
cytogenetics, loss of chromosome 7 is bad
severity of pancytopenia, all counts reduced is worse

Question 28

Contrast treatments for high risk and low risk MDS.

Answer 28

high: chemotherapy, bone marrow transplant
low: improve counts (ie. EPO), prevent iron overload

Question 29

Describe the features of a blast.

Answer 29

chromatin is thin, lighter, having a frosted glass appearance with high N;C ratio and nucleoli
blasts have varying size
(use context of disease to distinguish from reactive lymphocytes)

Question 30

Name the two diagnostic criteria for leukemia?

Answer 30

> 20% blast cells in the bone marrow or blood OR

evidence of recurring cytogenetic abnormality that is associated with AML

Question 31

Describe the basic principle of flow cytometry.

Answer 31

cells with specific receptors/proteins bind certain dyes and as tagged cells go through flow cytometry they give off characteristic color that can be used to created a distribution of cell types

Question 32

What characteristic chromosomal abnormalities associated with characteristic chromosomal abnormalities.

Answer 32

monosomy 7, del 5q, trisomy 8

Question 33

Describe the marrow of a person with CML.

Answer 33

very hyper cellular, increased G:E ratio, microcytes that tend to be small and have only one nuclear lobe
<20% blasts

Question 34

Blood smear with a mixture of mature and immature granulocyte precursors as well as basophils coupled with a buffy coat on the blood draw, and t(9;22) is consistent with which diagnosis?

Answer 34

chronic melodeons leukemia, with Philadelphia chromsome

Question 35

Hypolobulated neutrophils (pseudo-Pelger Huet cells) and marrow containing ringed sideroblasts in a patient who under went treatment with mutagenic drug treatment is likely which diagnosis?

Answer 35

myelodysplastic syndrome

note concurrent finding of del (7) is characteristic of MDS and chemo-related AML

Question 36

Blood smear with many large cells with high N:C ratio and immature appearing nuclei (blasts) is diagnostic of what blood disorder?

Answer 36

acute leukemia, confirmation would be accomplished by flow cytometry (AML v. ALL could be hypothesized based on age of patient)