CML

Question 1

Presentation

Answer 1

• Middle age
• FLAWS
• Splenomegaly
• Gout

Question 2

Bloods

Answer 2

• WCC increased
• high uric acid
• high Vit B12

Question 3

Morphology

Answer 3

“LEFT SHIT IN MYELOID MATURATION”:

• Hypercellular
• Granular
• Multiple nucleoli
• EOSINOPHILS and BASOPHILS
• mix of mature and immature cells

Question 4

Translocation WITH BREAKPOINTS

Answer 4

t(9;22)(q34;q11)

Question 5

Molecular genetics for (A) detecting and (B) monitoring

Answer 5

(A) FISH

(B) RQ-PCR
- the BCR gene has different breakpoints within a region, Do PCR at the RNA level to remove the introns, using the first exon of BCR as your breakpoint. Then you can do agarose gel analysis to identify which variant you have.

Question 6

How does the fusion work? How is it targeted therapeutically?

Answer 6

• BCR-ABL1 protein has a tyrosine kinase domain
• This has an ATP pocket, so ATP can enter and be used to phosphorylate tyrosine
• TKIs compete with ATP for the binding site, and don’t phosphorylate tyrosine.

Question 7

Why do some patients have resistance to TKIs?-

Answer 7

• mutation in the activation loop so the TKI can’t fit into the binding site