CML - Scott

Question 1

What is the initiating event in CML?

Answer 1

Philadelphia Chromosomal Translocation t(9;22)

Question 2

What is the oncogenic mechanism of CML?

Answer 2

Genomic translocation creates new gene encoding constitutively active tyrosine kinase

Question 3

What is the targeted molecular therapy based on the CML mechanism?

Answer 3

Tyrosine Kinase Inhibitors

Imantinib

Question 4

What causes CML?

Answer 4

Defects in neutrophil differentiation pathway

Question 5

What is the genetic basis for the defects in the neutrophil differentiation pathway that causes CML?

Answer 5

BCR-ABL1 fusion protein from the genomic translocation t(9;22) in a hematopoietic stem cell

Question 6

What are the characteristics of neutrophils?

Answer 6

First responders of the innate immune system
Most abundant WBC
Released from Bone Marrow
Migrate to site of infection
Kill microbes via several mechanisms

Question 7

What is the job of the neutrophil lineage?

Answer 7

Generating neutrophils with regulated proliferation that is critical for fighting infection with these short lived cells

Question 8

Describe the Neutrophil Lineage.

Answer 8

Hematopoietic Stem Cell –> Multipotential Progenitor –> Common Myeloid Progenitor –> Granulocyte Macrophage Progenitor –> Myeloblast –> Promyelocyte –> Myelocyte –> Metamyelocyte –> Band Cell –> Neutrophil

Question 9

Stem cells are capable of what?

Hematopoietic Stem Cell

Answer 9

Undergoes self-renewal
Pluripotent
Capable of Proliferation

Question 10

Progenitor cells are capable of what?
Multipotential Progenitor
Common Myeloid Progenitor
Granulocyte Macrophage Progenitor

Answer 10

Proliferation but not self-renewal
Multipotent
Capacity narrows

Question 11

Committed cells are capable of what?
Myeloblast
Promyelocyte
Myelocyte
Metamyelocyte
Band Cell
Neutrophil

Answer 11

Do not proliferate

Have only 1 fate (next cell in neutrophil path)

Question 12

Extracellular signaling from the bone marrow regulates what?

Answer 12

Self-Renewal and Proliferation

Question 13

Define BCR

Answer 13

Breakpoint Cluster Region gene

Question 14

Define ABL1

Answer 14

Ableson Tyrosin Kinase gene

Question 15

Once a BCR-ABL1 genomic translocation occurs in the hematopoietic stem cell, what happens to the daughter cells?

Answer 15

BCR-ABL1 fusion protein in hematopoietic stem cell is constitutively active tyrosine kinase that activates proliferation and blocks apoptosis in all progeny cells

Question 16

Constitutively active BCR-ABL1 ___________ confer ability to self renew.
Does or Does Not

Answer 16

Does Not

Question 17

BCR-ABL1 progenitor cells ___________ self renew.

Do or Do Not

Answer 17

Do Not

Question 18

BCR-ABL1 progenitor cells ___________ continue to differentiate.
Do or Do Not

Answer 18

Do

Question 19

In chronic phase CML, what is the outcome of the expansion of progenitor and committed cells?

Answer 19

Mature cells are still produced and disease is relatively mild

Question 20

What additional changes are needed to progress from Chronic CML to Blast Phase?

Answer 20

GMP acquired self-renewal capability through Wnt-B catenin signaling being activated
Differentiation is blocked by inhibition of CEBPa translation

Question 21

In blast phase CML, what is the outcome of the extreme expansion of blasts?

Answer 21

Production of functional mature cells is blocked which causes severe disease

Question 22

What is the BCR-ABL translocation?

Answer 22

t(9;22)(q34;q11) Philadelphia Chromosome

Question 23

How does this translocation arise?

Answer 23

Double stranded breaks occur in two chromosomes at specific breakpoints
Non-homologous end joining mechanism is used to repair the DNA
=> End of different chromosomes are joined

Question 24

What are the characteristics BCR-ABL1 kinase?

Answer 24

BCR: Coiled-Coil Domain with Tyrosine 177
ABL: Constitutively Active Tyrosine Kinase
Active in cytoplasm

Question 25

What are the characteristics of BCR normally?

Answer 25

Functional Domain: Ser/Thr kinase domain

Normal Function: Role in inhibition of some inflammatory responses

Question 26

What are the characteristics of ABL1 normally?

Answer 26

Functional Domain: Tyrosine Kinase
Kinase is held inactive by Myristate unless activated by external signals
Normal Function: Role in DNA repair and cytoskeleton organization; mainly nuclear

Question 27

What does the BCR coiled-coil domain promote?

Answer 27

Dimerization necessary for activation

Question 28

How does the BCR-ABL Tyrosine-177 affect cell signaling?

Answer 28

Phosphorylation of Tyrosine-177 creates a new binding site for intracellular signaling proteins leading to dysregulated proliferation and protection from apoptosis

Question 29

How does Imatinib work?

Answer 29

Inactivates ABL1 kinase by blocking ATP binding so that the substrate can no longer be phosphorylated

Question 30

Cells rely on the mutant BCR-ABL for proliferation and anti-apoptotic signaling. What happens when Imatinib inactivates the BCR-ABL?

Answer 30

Apoptosis

Question 31

What are the limitations of Imatinib?

Answer 31

1) Secondary resistance due to BCR-ABL mutations
2) Not effective against blast phase
3) CML stem cells are resistant to tyrosine kinase inhibitors

Question 32

Due to the limitations of Imatinib and quiescent stem cells, how must Imatinib be taken?

Answer 32

FOR LIFE!