CML

Question 1

Chronic Myelogenous Leukemia is what kind of disorder?

Answer 1

• myeloproliferative
  
  • characterized by increased proliferation of the granulocytic lineage cells without the loss of their ability to divide

Question 2

Key features of CML in patient history:

Answer 2

• incident discovery by CBC
• fatigue
• weight loss
• easy bruising
• low grade fevers

Question 3

Key features of CML in patient blood work:

Answer 3

• elevated WBC

Question 4

Which WBCs are normally elevated in CML?

Answer 4

• neutrophils and lymphocytes

Question 5

Key features of CML in patient physical exam:

Answer 5

• normal
• pallor (paleness)
• splenomegaly (enlarged spleen)

Question 6

Why do some patients present with an enlarged spleen in CML?

Answer 6

• Alterations in hematopoeitic stem cells and their interactions with the bone marrow stem cell niche allow abnormal progenitor trafficking.
  
  • Abnormal cells take up residence in the spleen and proliferate.

Question 7

CML is caused by:

Answer 7

• a chromosomal disorder
  
  • balanced reciprocal translocation between chromosomes 9 and 22 (no loss of genetic information)
  • “Philadelphia Chromosome”

Question 8

Breakpoints for the balanced reciprocal translocation that gives rise to CML are located where?

Answer 8

• within the intron regions of the BCR gene of chromosome 22 and the intron regions of the Abl gene on chromosome 9.

Question 9

How does the balanced reciprocal translocation give rise to CML?

Answer 9

• Abl is a cytoplasmic tyrosine kinase normally inhibited by a region of itself.
• Inhibitory region is lost in translocation, and Abl gains a domain from BCR that facilitates dimerization of BCR-Abl with another BCR-Abl.
  
  • Leads to a constitutively active Abl.
  • No regulation.

Question 10

c-Abl is:

Answer 10

• a nuclear and cytoplasmic tyrosine kinase

Question 11

c-Abl is important for:

Answer 11

• cell survival, cell proliferation, DNA repair

Question 12

When compared to c-Abl, BCR-Abl is:

Answer 12

1. constitutively active.
2. trapped primarily in the cytoplasm.
   
   • therefore it is NOT in the nucleus and not able to carry out its DNA repair function.

Question 13

The BCR-Abl mutation first occurs in what type of cell?

Answer 13

• hematopoietic stem cells

Question 14

BCR-Abl RT-PCR Banding in Normal Patient:

Answer 14

• Single 808 bp fragment in normal WBC

Question 15

BCR-Abl RT-PCR Banding in CML patient:

Answer 15

• Single 808 bp fragment PLUS 310 or 385 bp fragment.

Question 16

Which lanes have a BCR-Abl protein indicative of CML?

Answer 16

• lanes 3 and 5

Question 17

What is the karyotype of CML

Answer 17

46XY, t(9;22)(q34;q11)

“Philadelphia Chromosome”

Question 18

Imatinib is:

Answer 18

• a tyrosine kinase inhibitor (TKI).
• inhibits the binding of ATP to the BCR-Abl tyrosine kinase; tumor cell cannot proliferate and dies.