Haematology: imatinib resistance in CML: practice question

A Pathology question in the style of the NEET PG paper. Answer it first, then read why the right option is right and why each of the others is wrong.

Try it

Pathology · Haematology: imatinib resistance in CML

Sample item

A 40-year-old man with chronic myeloid leukaemia in chronic phase initially responded to imatinib. After 2 years his BCR-ABL transcript level rises and the white count climbs again. Sequencing shows a T315I change. What is the mechanism of resistance?

Original practice item, not a recalled exam question. Nothing here is recorded.

The answer and the reasoning

D. Point mutation in the ABL kinase domain that blocks drug binding

The commonest cause of acquired imatinib resistance is a point mutation within the ABL kinase domain that prevents the drug from binding. The T315I gatekeeper mutation resists several first and second generation inhibitors, so a different inhibitor is needed.

Option by option

  • A. Deletion of the Philadelphia chromosome in marrow stroma

    The Philadelphia chromosome is an acquired change in leukaemic cells and not in stroma, and its loss would not explain rising transcripts.

  • B. Loss of the BCR-ABL fusion gene from the clone

    If the fusion were lost, transcript levels would fall rather than rise.

  • C. Acquisition of a JAK2 mutation replacing BCR-ABL

    JAK2 mutations belong to polycythaemia vera, essential thrombocythaemia and myelofibrosis, not to CML resistance.

  • D. Point mutation in the ABL kinase domain that blocks drug binding (correct)

    Correct. Kinase domain mutations such as T315I prevent binding while keeping the oncogenic kinase active.

Source note: Original NextPrep sample item — pending expert review. This item is original practice material awaiting independent expert review, so confirm important facts in a standard textbook.

More Pathology questions

Questions about this Pathology question

What is the answer to this Pathology question?

The best answer is D, Point mutation in the ABL kinase domain that blocks drug binding. The commonest cause of acquired imatinib resistance is a point mutation within the ABL kinase domain that prevents the drug from binding.

Why is "Deletion of the Philadelphia chromosome in marrow stroma" not the answer?

The Philadelphia chromosome is an acquired change in leukaemic cells and not in stroma, and its loss would not explain rising transcripts.

Why is "Loss of the BCR-ABL fusion gene from the clone" not the answer?

If the fusion were lost, transcript levels would fall rather than rise.

Why is "Acquisition of a JAK2 mutation replacing BCR-ABL" not the answer?

JAK2 mutations belong to polycythaemia vera, essential thrombocythaemia and myelofibrosis, not to CML resistance.

What concept does this question test?

It tests Haematology: imatinib resistance in CML in Pathology. The T315I gatekeeper mutation resists several first and second generation inhibitors, so a different inhibitor is needed.

How hard is this question?

We tag it as a multi-step question: it asks you to combine more than one idea. The tag is our own editorial judgement, not an official difficulty rating, so read the reason for every option, not only the answer.

How should I study Haematology: imatinib resistance in CML?

Learn each disease as a bundle: cause, key histology, markers, and the clinical hallmark. Then use the flashcards and the other Pathology questions on this site to test what stuck.

Is this a real NEET PG question?

No. It is an original practice item (editorial status: sample, version 1). NextPrep does not publish recalled or leaked questions, and independent faculty review of this item has not been completed yet, so confirm important facts in a standard textbook.