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IHO Week 4 (MJ) > CML Module > Flashcards

CML Module Flashcards

1
Q

Chronic Myeloproliferative Disorders: Definition

A

Malignant proliferation of myeloid cells (NOT blasts, but maturing cells) in blood and bone marrow

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2
Q

The 4 myeloproliferative disorders

A

Chronic Myeloid Leukemia (CML)
Polycythemia Vera (PV)
Essential Thrombocythemia (ET)
Myelofibrosis (MF)

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3
Q

What is proliferating in CML?

A

Neutrophils

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4
Q

What is proliferating in PV?

A

Red cells

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5
Q

What is proliferating in ET?

A

platelets

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6
Q

What is proliferating in MF?

A

Everything

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7
Q

Features of myeloproliferative disorders (general)

A 
Adults
Long clinical course
Increased WBC with left shift
Hypercellular marrow
Big spleen
Mutated Tyrosine kinases
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8
Q

What can myeloproliferative disorders develop into?

A

Acute leukemia

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9
Q

Chronic Myeloid Leukemia

A

Neutrophilic leukocytosis
Basophilia
Philadelphia Chromosome
Three phases

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10
Q

Lab Findings of CML

A 
Increased WBC
Neutrophilia with Left Shift
Basophilia
Decreased Hgb
Increased platelets
Decreased LAP
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11
Q

LAP

A

enzyme in neutrophils.
In benign process - high.
Malignant - low.

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12
Q

Philadelphia Chromosome

A

Chunk of 9 breaks off - adds to 22.
22 is the Philadelphia chromosome
Makes active TYK

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13
Q

Symptoms of CML

A

Slow onset
Fever, fatigue, night sweats
abdominal fullness (splenomegaly)

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14
Q

Signs of CML

A

Big spleen and big liver

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15
Q

3 phases of CML

A

Chronic, accelerated, blast crisis

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16
Q

Chronic CML

A

Stable counts, controlled

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17
Q

Accelerated CML

A

50% from chronic.

Unstable. Blast crisis in 6-12 months

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18
Q

Blast Crisis

A

50% for chronic.
Acute leukemia of either lineage.
High mortality

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19
Q

Remission of CML

A

Best detected by PCR. No BCR-ABL1

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20
Q

About Polycythemia Vera

A

High RBCs (makes blood sludgy)
Different from secondary polycythemia (altitude)
Thrombosis and hemorrhage
JAK2 mutation

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21
Q

Polycythemia mean…

A

increased red cell mass

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22
Q

Primary polycythemia

A

intrinsic myeloid cell problem

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23
Q

secondary polycythemia

A

increased EPO

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24
Q

Clinical signs of PV

A

headache, pruritis, dizziness

Thrombosis, infarctions

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25
Q

Symptoms of PV

A

big spleen and liver. Flushing.

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26
Q

JAK2 Pathway

A

Unique pathway that does not involve secondary messengers. Brings growth factors to nucleus and stimulates division.

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27
Q

JAK STAT in PV

A

Mutated JAK2

Inhibitory portion does not work - continually signaling

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28
Q

Treatment of PV

A

phlebotomy

Maybe myelosuppressive drugs

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29
Q

Prognosis

A

Median survival 9-14 years
Death from thrombosis or hemorrhage
Leukemic transformation in some patients

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30
Q

About Essential Thrombocythemia

A

Very high platelet count
Young women
Diagnosis of exclusion
Thrombosis and hemorrhage

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31
Q

Diagnostic criteria for ET (platelet)

A

Platelet count > 600,000

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32
Q

Diagnostic criteria for ET (Hgb)

A

> 13 or RBC mass normal

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33
Q

Diagnostic criteria for ET

A

Platelets count >600,000
RBC mass normal or Hgb >13
No Philadelphia chromosome or marrow fibrosis

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34
Q

Signs and Symptoms of ET

A

Bleeding, thrombosis (even though lots of platelets - they aren’t working)
Purpura, bruising, pallor, tachycardia, big spleen

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35
Q

Treatment of ET

A

platelet pheresis
Maybe myelosuppressive drugs
Aspirin

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36
Q

Prognosis of ET

A

5-8 years
Death from thrombosis or hemorrhage
Leukemic transformation

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37
Q

Chronic Myelofibrosis course

A

panmyelosis — then marrow fibrosis

Extramedullary hematopoiesis

38
Q

Hallmark of Myelofibrosis (Smear)

A

Teardrop red cells

39
Q

Signs and Symptoms of MF

A

LUQ fullness, weakness, fatigue, palpitations

Splenomegaly, pallor, tachy

40
Q

Treatment of MF

A

Supportive

Maybe myelosuppressive drugs

41
Q

Prognosis of MF

A

3-5 years
Death from marrow failure
Leukemic transformation possible

42
Q

Why is the SH3 domain important?

A

It is a common motif to establish multi enzyme complexes

43
Q

BCR-ABL1 mimics what?

A

Growth factor activation

44
Q

Mechanism of Imatinib

A

ATP binding site competitive inhibitor

45
Q

SE of Imatinib

A 
muscle cramps
asthenia (wasting syndrome)
edema
skin fragility
diarrhea
tendon and ligament abnormalities
46
Q

Why does Imatinib have broad SE?

A

TYK have many families. May work on many different ‘branches’

47
Q

What is so special about Imatinib?

A

It is a small molecule drug that binds at the ATP binding site for kinase activity, rather than selectively inhibiting the BCR-ABL1 protein.
Has less collateral damage than one would think

48
Q

What enzyme metabolizes Imatinib

A

CYP3A4 (grapefruit juice = bad)

49
Q

Resistance to Imatinib

A

Altered metabolism CYP3A4
Altered membrane transport
Loss of p53 (which confers resistance to apoptosis)
Over expression of BCR-ABL1
Point mutations, especially in binding domain

50
Q

Biggest mutation in CML

A

T313I

51
Q

What happens in T315I mutation

A

Loss of binding parter, big thumb sticks out of binding pocket.
Imatinib can no longer keep from phosphorylating and cell signaling will continue as a result.

52
Q

How common is T315I?

A

30% of cancers resistant to Imatinib have this mutation.

53
Q

Nilotinib

A

Induces deeper and faster remissions

lower levels of BCR-ABL transcripts

54
Q

Side effects of Nilotinib?

A

Same as Imatinib

55
Q

How does Nilotinib work?

A

Has a hydrophobic binding pocket with fluorine group

56
Q

Does Nilotinib work with T315I resistance?

A

No

57
Q

Dasatinib

A

Works against BCL-ABL1 and Src

Active against point mutations, except T315I

58
Q

SE of Dasatinib

A

fluid retention and pulmonary HTN

Inhibits some threonine and serine kinases (DIRTY)

59
Q

Bosutinib

A

Active against BCR-ABL1 and Src

Works on most point mutations, except T315I

60
Q

Ponitinib

A

Designed based on T315I

Active against this mutation

61
Q

SE of Ponitinib

A

Causes clots and arterial fibrosis that can be fatal

62
Q

Treatment of CML is an example of…

A

successful molecular medicine

63
Q

Initiating event of CML?

A

Translocation at (9;22)

64
Q

What happens with t(9:22)

A

Genomic translocation creates new gene encoding for an active tyrosine kinase

65
Q

What differentiation pathway does CML affect?

A

Neutrophil

66
Q

Neutrophils arise from…

A

hematopoietic stem cells –> then Multipotential progenitor and Common myeloid progenitor

67
Q

3 stages of Neutrophil development

A

Stem cell - undergoes self renewal and proliferation
Progenitor - just proliferation
Committed - neither - one fate

68
Q

Self renewal and proliferation are tightly regulated by..

A

extracellular signaling from marrow. Immune system.

ensures that appropriate number of neutrophils are produced.

69
Q

BCR-ABL1 is a….

A

constitutively active tyrosine kinase - activates proliferation and blocks apoptosis in the absence of extracellular signals.

70
Q

Where does the BCR-ABL1 mutation arise?

A

Hematopoietic stem cell

Passed down to all progeny

71
Q

Expression of BCR-ABL1 fusion protein disrupts….

A

normal neutrophil differentiation

72
Q

BCR-ABL and selective advantage?

A

Progenitor cells proliferate more and survive longer

Acquire more mutations to become oncogenic

73
Q

Do constitutively active BCR-ABL1 cells self renew?

A

NO.. still mature

74
Q

How does CML develop into the accelerated/blast phase?

A

GMP acquires ability to self renew. Blocks differentiation. Results in huge expansion on immature cells

75
Q

What does b-catenin do?

A

transcription factor activated by WNT extracellular ligand

Self renewal of stem cells

76
Q

Mutation in b-catenin leads to…

A

Blast crisis

77
Q

What happens in the translocation event?

A

Genomic DNA is physically rearranged between 9 and 22

78
Q

Which one is the philadelphia chromosome (9 or 22)

A

22 (22q-)

79
Q

Mechanism for translocation?

A

non-homologous end joining

p210 or p190

80
Q

Normal role of BCR

A

inhibition of inflammatory response

81
Q

Normal role of ABL1

A

Kinase used for DNA repair, cytoskeletal organization

82
Q

what normally regulates ABL1 activity

A

myristate, a long chain FA

83
Q

ABL is mainly located _____, BCR-ABL is _______

A

nuclear, cytoplasmic

84
Q

the ______ domain of BCR promotes dimerization

A

coil-coil

85
Q

_____ attachment is lost from ABL1 in mutation

A

myristate

86
Q

Tyrosine 177

A

BCR phosphorylation creates new binding site on Y177 (in mutated protein)

87
Q

Signaling in normal ABL

A

myristate blocks, then extracellular signaling, opens conformation, dimerization occurs allowing transphosporylation
Phos TK are the platforms for signaling

88
Q

Signaling in BCR-ABL1

A

No myristate so open (no signaling needed), coil coil of BCR promotes dimerization.

89
Q

Why is Y177 only subject to phosphorylation in mutation?

A

BCR isn’t a tyrosine kinase normally

90
Q

Why does the inactivation of BCR-ABL result in apoptosis?

A

Mutant cells depend on the pathway

91
Q

Why must imatinib be taken for life?

A

Doesn’t work against stem cells. If stop, quiescent stem cells will restart the disease

IHO Week 4 (MJ) (10 decks)

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