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MOD 3 > Myeloid Neoplasms > Flashcards

Myeloid Neoplasms Flashcards

1
Q

What are the two types of hematopoietic neoplasms?

A
  1. Myeloid neoplasms
  2. Lymphoid neoplasms
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2
Q

List the three important myeloid neoplasms

A
  1. Acute Myeloid Leukemia (AML)
  2. Myeloproliferative Neoplasms (MPN)
  3. Myelodysplastic Syndroms (MDS)
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3
Q

For Myeloid Neoplasms, list:

  • two common features
  • where they generally arise
  • description of the group of disorders
A
  • monoclonal, origin from HSCs or progenitor cells
  • generally arise in bone marrow
  • very heterogenous** **group of disorders, with considerable overlap
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4
Q

From the common myeloid progenitor, list the 4 types of cells it gives rise to

A
  1. Megakaryocyte
  2. Erythrocyte
  3. Mast cell
  4. Myeloblast
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5
Q

List the 4 cells a myeloblast gives rise to

A
  1. basophil
  2. neutrophil
  3. eosinophil
  4. monocytes –> macrophage
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6
Q

What makes up the bone marrow stroma? List two important functions

A

Bone marrow stroma:

stromal cells, ECM molecules, reticulin framework

  1. Provides a scaffold onto which the developing cells are bound
  2. helps direct traffic of the cytokines that regulate hematopoiesis
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7
Q

For AML, list the following:

  • type of problem
  • what you see as a result
  • acute or chronic
A

AML:

  • problem of differentiation AND proliferation
  • high WBC (blasts) or pancytopenia (decreased count)
  • acute
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8
Q

For MPN, list the following:

  • type of problem
  • what you see as a result
  • acute or chronic
A

MPN:

  • problem of proliferation (they have no problem maturing and differentiating)
  • leukocytosis, erythrocytosis, thrombocytosis (increased count)
  • chronic
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9
Q

For MDS (Myelodysplastic Syndrome), list the following:

  • type of problem
  • what you see as a result
  • acute or chronic
A

MDS:

  • Problem of differentiation (abnormal maturation, ineffective hematopoiesis)
  • cytopenias, pancytopenia
  • chronic
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10
Q

Myeloid neoplasms, like other malignancies, tend to evolve over time to more aggressive forms of disease. For example, CML can transform to acute lymphoblastic leukemia. What does this indicate?

A

Indicates that the CML originated from a transformed pluripotent hematopoietic stem cell

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11
Q
  • definition of AML
  • cause of AML
  • effect on cells
A
  • neoplasm of hematopoietic progenitors
  • cause: acquired genetic abnormalities (somatic mutation) that interfere with proliferation and differentiation
  • accumulation of blasts in the marrow, resulting in marrow failure
    • anemia, neutropenia, and thrombocytopenia
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12
Q

3 main ways AML arises

A
  1. De novo: in absence of risk factors
  2. AML arising with pre-existing genetic factors
    * Fanconi’s anemia, Down’s, Kostmann syndrome, Wiskott Aldrich syndrome, Li-Fraumeni syndrome
  3. AML arising after certain exposures
  • radiation
  • toxic chemicals
  • therapy related: chemo (topoisomerase II inhibitors, alkylating agents), radiation therapy
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13
Q

Describe the acute presentation of AML and relate the characteristics to clinical signs

A
  • ill patient for weeks/few months
  • symptoms related to bone marrow failure:
    • anemia: fatigue
    • neutropenia: infection, fever (opportunistic–fungi, pseudomonas)
    • thrombocytopenia: spontaneous bleeding
  • bone pain
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14
Q

DIC presents in AML. Which particular type is most common?

A

AML t(15;17)

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15
Q

chloroma (myeloid sarcoma)

A

AML occasionally presents as such: a localized soft-tissue mass

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16
Q

Extra-medullary involvement of AML

A

AML with monocytic differentiation often infiltrate the skin (leukemia cutis) and gingiva)

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17
Q

Lab abnormalities in AML:

A

CBC:

  • number of blasts in blood is highly variable
  • increase WBC with numerous blasts (leukostasis)
  • decreased WBC (leukoenia) /// pancytopenia
    • very few circulating blasts, but marrow packed with blasts

Other lab abnormalities:

  • increase in uric acid (reflection of high cell turnover)
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18
Q

explain the molecular pathogenesis of AML t(8;21)

A

example of a somatic mutation in transcription factors required for normal myeloid differentiation (maturation):

  • disruption of CBFa (RUNX1) gene
    • normally encodes a protein that binds another protein to form a TF needed for normal hematopoiesis
  • t(8;21) creates a chimeric gene BLOCKS the maturation of myeloid cells
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19
Q

Tyrosine kinases:

  • normal role
  • what happens in AML
  • example mutation
A
  • involved in regulation of cell survival and proliferation
  • AML: activating mutations lead to INCREASED proliferation
  • example: FLT3 mutations
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20
Q

List the genetic alterations in AML that are **Class 1 Proliferation **(5)

A
  1. FLT3
  2. KIT
  3. RAS
  4. PTPN11
  5. JAK2
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21
Q

Genetic alterations in AML-Class II Differentiation (5)

A
  1. PML-RARA
  2. RUNX-RUNX1t1
  3. CBFB-MYH11
  4. MLL fusions
  5. CEBPA
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22
Q

How do we diagnose AML? (3)

A
  1. Morphology (microscopic examination of blood and bone marrow)
  2. Immunophenotyping
  3. Cytogenetics/Molecular Genetics
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23
Q

Two types of immunophenotyping

A

Flow cytometry, immunohistochemistry

(FC is good for leukemias vs carcinomas since dealing with wet specimans//cells floating in suspension, vs. solid tumors

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24
Q

3 types of cytogenetics/molecular genetics

A

Karyotype, FISH, PCR

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25
Q

AML definition: % blasts

A

blasts > or = to 20% in blood or bone marrow

(blast count can be lower in some AML defining translocations, i.e. 8;21 and 15;17

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26
Q

in AML, describe how blasts are heterogenous in appearance

A

myeloblasts, monoblasts, with/without Auer rods

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27
Q

What are auer rods, and what are they indicative of

A

Aurer rods are crystal aggregates of MPO. They are sometimes seen in acute myelogenous leukemia

(myeloblasts are usually characterized by positive cytoplasmic staining for myelopoeroxidase)

28
Q

In flow cytometry, what are 5 myeloid-specific antigens?

A
  • CD13
  • CD33
  • CD117
  • CD11b, CD11c
  • MPO
29
Q

What are the 4 main categories of AML classification?

A
  1. AML associated with particular genetic abberations
    e.g. t(8;21), inv(16), t(15;17), better prognosis
  2. AML arising after a myelodysplastic disorder, or with MDS- like features: usually poor prognosis
  3. Therapy-related AML
  4. AML, NOS (not otherwise specified): “Wastebasket: category
    AMLs lacking any of these features, classified based on
    differentiation and lineage
30
Q

t(15;17)

what gene gets affected

A

**Acute promyelocytic leukemia **

example of an AML with recurrent genetic abnormality

involves translocations of the retinoic acid receptor (RAR): results in PML/RARA fusion gene

RAR disruption blocks maturation and promyelocytes (blasts) accumulate

31
Q

Why is AML with t(15;17) a medical emergency

A

Abnormal promyelocytes (blasts) that build up contain numerous primary granules that increase the risk of DIC

32
Q

treatment of acute promyelocytic leukemia t(15;17)

A

all-trans-retinoic acid (ATRA)

a vitamin A derivative, binds the altered receptor and causes the blasts to mature into neutrophils

33
Q

List the 5 main myeloproliferative neoplasms

A
  1. Chronic Myelogenous Leukemia
  2. Polycythemia Vera
  3. Essential Thrombocytosis
  4. Primary Myelofibrosis
  5. Systemic Mastocytosis
34
Q

tyrosine kinases in Myeloproliferative Neoplasms

A

constitutively activated: they bypass normal controls and lead to growth factor INDEPENDENT proliferation

thus: this is a problem with proliferation–differentiation is intact

35
Q

What do you see in the peripheral blood in Chronic Myelogenous Leukemia?

A

Leukocytosis with left shift (expansion of white cell precursors)

  • neutrophilia, basophilia, and/or eosinophili
  • often anemia and thrombocytosis
36
Q

Aside from the peripheral blood abnormalities, what are two other important findings in CML?

A

Bone Marrow: hypercellular bone marrow with maturation

Splenomegaly: enlarging spleen suggests progression to accelerated phase of disease

37
Q

What type of mutation drives Chronic Myeloid Leukemia?

A

Driven by t(9;22) Philadelphia Chromosome, which generates a BCR-ABL fusion protein with increased tyrosine kinase activity

38
Q

Chronic myeloid leukemia is neoplastic proliferation of mature myeloid cells. Which cells in particular are characteristically increased?

A

granulocytes and their precuroses; BASOPHILS

39
Q

What do you expect to see in a bone marrow biopsy of CML?

A

You will see a packed marrow filled with cells, but the key thing is you will see a MIXTURE of cells. This is because the cells are still differentiating (unlike in acute myeloid leukemia); there is just abnormal proliferation

40
Q

blast crisis in CML

A

natural history of CML:

chronic phase (3 years) –> accelerated phase (count starts to deteriorate) –> blast crisis (months)

blast crissi is CML that transforms to acute leukemia (AML or ALL)

*MPNs may originate in multipotent myeloid progenitors that give rise to a pure myeloid process, or in pluripotent hematopoietic stem cells that give rise to both lymphoid and myeloid cells

41
Q

It is unlikely that CML will progress to blast crisis, because the disease is well controlled. What are the 5 important treatments?

A

hydroxyurea

interferon +/- cytosine arabinoside

Allogeneic bone marrow transplant

Imatinib mesylate (tyrosine kinase inhibitor)

dasatinib, nilotinib (second generation TKI)

42
Q

Polycythemia vera:

  • what is the problem
  • what is the mutation type
A
  • neoplastic proliferation of mature myeloid cells, especially RBCs
  • associated with JAK2 kinase mutation: JAK2 participates in JAK/STAT pathway, which lies downstream of multiple hematopoietic growth factor receptors, including EPO receptor
43
Q

clinical symptoms of polycythemia vera:

A

due to hyperviscosity of blood (from high red blood cell count!)

  • blurry vision and headache
  • increased risk of venous thrombosis (hepatic vein, portal vein, and dural sinus)
  • flushed face due to congestion
  • itching after bathing (histamine release from increased mast cells)
44
Q

How can you distinguish polycythemia vera from reactive polycythemia?

A

EPO

PV: low EPO (negative feedback); SaO2 normal

Reactive polycythemia: high EPO (due to high altitude or lung disease); SaO2 is low

also see high EPO in tumor i.e. renal cell carcinoma

45
Q

Essential Thrombocythemia

  • what is the problem
  • associated with what type of mutation
A
46
Q
  • neoplastic proliferation of mature myeloid cells, especially platelets
  • associated with a JAK2 kinase mutation
A
47
Q

Symptoms in Essential Thrombocythemia

A

related to an increased risk of bleeding (platelets not functioning) and/or thrombosis (platelets overfunctioning):

-rarely progresses to marrow fibrosis or acute leukemia

48
Q

Why is there no sigfnicant risk for hyperuricemia or gout in Essential Thrombocythemia?

A

Hyperuricemia or gout is associated with high cell turnover; in ET, you don’t have excess turnover- just pieces of cytolasm blebbing off for platelets.

49
Q

Compare the following for PV and ET:

  • increase primarily in
  • splenomegaly
  • myelofibrosis potential
  • AML transformation
A

PV:

  • increase primarily in RBCs
  • splenomegaly** COMMON**
  • myelofibrosis potential** 15-20%**
  • AML transformation uncommon

ET:

  • increase primarily in** PLATELETS**
  • splenomegaly **in minority **
  • myelofibrosis potential is **infrequent **
  • AML transformation

PV:

  • increase primarily in RBCs
  • splenomegaly COMMON
  • myelofibrosis potential 15-20%
  • AML transformation **is uncommon **
50
Q

Post-polycythemic myelofibrosis (spent phase): 3 main characteristics

A
  • overt bone marrow fibrosis: reticular fibers
  • worsening splenomegaly due to extramedullary hematopoiesis
  • leukoerythroblastic blood smear (tear drop RBCs, nucleated RBCs, and immature granulocytes
51
Q

Primary myelofibrosis

  • problem
  • mutation
A
  • neoplastic proliferation of mature myeloid cells, especially megakaryocytes
  • JAK2 kinase mutation (50%); MP mutation (1-5%)
52
Q

For each Myeloproliferative Neoplasm, list the mutation:

1) CML
2) P vera
3) Essential Thrombocythemia
4) Primary Myelofibrosis

A

1) CML: BCR/ABL
2) P vera: JAK2 V617F or other JAK2 mutation
3) ET: JAK2, MPL, or Calreticulin
4) Primary Myelofibrosis: JAK2, MPL, or Calreticulin

most of these are tyrosine kinase pathways

53
Q

5 key points of myeloproliferative neoplasms

A

1) PROLIFERATION: increased proliferative drive in bone marrow : results in high WBC count with hypercellular bone marrow
2) EXTRAMEDULLARY HEMATOPOIESIS
3) TRANSFORMATION TO SPENT PHASE: bone marrow fibrosis and peripheral blood cytopenias
4) VARIABLE TRANSFORMATION TO ACUTE LEUKEMIA
5) MOLECULAR TESTS FO RTYROSINE KINASE MUTATIONS: important for diagnosis and the selection therapy; availability of kinase inhibitors

54
Q

Most common hematologic malignancy in the elderly

A

Myelodysplastic Syndromes (MDS)

55
Q

What is Myelodysplastic Syndrome? (4)

A
  • Clonal stem cell disorder
  • abnormal maturation (uni or multi lineage dysplasia)
  • ineffective hematopoiesis resulting in cytopenias
  • Susceptibility to leukemic transformation (AML)
56
Q

Explain the ineffect hematopoiesis that occurs in myelodysplastic syndrome

A
  • the clonal stem cells can differentiate, but in an ineffective manner
  • the abnormal maturing cells accumulate in the bone marrow, partly or completely replacing normal hematopoiesis
  • resulting in anemia, leukopenia, and/or thrombocytopenia
57
Q

Pathogenesis of MDS: 4 genetic abnormalities

A

1) Epigenetic factors: mutations that regulate DNA methylation and histone modifications; similar to AML mutations
2) RNA splicing factors: mutations involving the 3’ end of RNA splicing machinery
3) TFs: mutations in ones needed for normal myeloid differentiation
4) Tumor suppressor gene TP53 in 10% of MDS cases

58
Q

Tyrosine kinases in MDS

A

activatin mutations in Tks are NEARLY ABSENT IN MDS!!! (unlike in AML and MPNs)

59
Q

3 clinical features of MDS:

A

1) disease of older adults: present with fatigue and mild anemia
2) discovered incidentally on routine blood testing
3) cytopenias resulting in weakness, infections, and hemorrhages

60
Q

5q- syndrome

A

specific subtype of MDS:

  • resulting in ineffective erythropoiesis
  • occurs more often in elderly woman
  • macrocytic anemia and thrombocytosis (high platelet count)
61
Q

What must you do when diagnosing MDS?

A

you MUST rule out other disorders i.e. check serum B12, RBC folate, serum iron, TSH, copper levels

62
Q

Characteristic morphologic changes in bone marrow and peripheral blood in MDS:

A
  • abnormal bi-lobed pelger huet-like neutrophil
  • hypogranular neutrophil
  • erythroid dysplasia
63
Q

MDS treatment

A
  • supportive: transfusions, antibiotics
  • MDS is particularly resistant to conventional chemo
  • DNA methylation inhibitors
  • Thalidomide-like drugs: Lenalidomide in 5q syndrome
  • allogenic HSC transplantation (young pts)
64
Q

clonal multipotent stem cell that can differentiate but in an ineffective manner

A

MDS

65
Q

Molecular pathogenesis of MDS:

A

increased apoptotic cell death

66
Q

Does MDS progress to AML?

A

YES, often

MOD 3 (19 decks)

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