Molecular biology and genetics: insertional mutagenesis in gene therapy: practice question

A Biochemistry 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.

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Biochemistry · Molecular biology and genetics: insertional mutagenesis in gene therapy

Sample item

Some children with X-linked severe combined immunodeficiency who received gene therapy with a retroviral vector later developed T-cell leukaemia. Which mechanism was responsible?

AImmune rejection of the corrected cells provoking a lymphoproliferative responseBLoss of the vector promoter, which silenced the therapeutic geneCReversion of the corrected gene to its original mutant sequenceDVector integration near a proto-oncogene, which activated its expression

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

The answer and the reasoning

D. Vector integration near a proto-oncogene, which activated its expression

Gamma-retroviral vectors integrate preferentially near active promoters. In these trials the vector landed next to proto-oncogenes such as LMO2 and its enhancer switched them on, causing clonal T-cell leukaemia. Later vector designs removed strong enhancers to lower this risk.

Option by option

A. Immune rejection of the corrected cells provoking a lymphoproliferative response
Rejection of corrected cells does not explain clonal leukaemia.
B. Loss of the vector promoter, which silenced the therapeutic gene
Silencing of the transgene would reduce benefit and does not cause malignancy.
C. Reversion of the corrected gene to its original mutant sequence
Reversion would restore immunodeficiency, not cause leukaemia.
D. Vector integration near a proto-oncogene, which activated its expression (correct)
Correct. Insertional mutagenesis activated a nearby proto-oncogene.

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.

Questions about this Biochemistry question

What is the answer to this Biochemistry question?

The best answer is D, Vector integration near a proto-oncogene, which activated its expression. Gamma-retroviral vectors integrate preferentially near active promoters.

Why is "Immune rejection of the corrected cells provoking a lymphoproliferati…" not the answer?

Rejection of corrected cells does not explain clonal leukaemia.

Why is "Loss of the vector promoter, which silenced the therapeutic gene" not the answer?

Silencing of the transgene would reduce benefit and does not cause malignancy.

Why is "Reversion of the corrected gene to its original mutant sequence" not the answer?

Reversion would restore immunodeficiency, not cause leukaemia.

What concept does this question test?

It tests Molecular biology and genetics: insertional mutagenesis in gene therapy in Biochemistry. In these trials the vector landed next to proto-oncogenes such as LMO2 and its enhancer switched them on, causing clonal T-cell leukaemia. Later vector designs removed strong enhancers to lower this risk.

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 Molecular biology and genetics: insertional mutagenesis in gene therapy?

Build one table of enzyme deficiency, disease, inheritance and key finding, then revise it by spaced recall. Then use the flashcards and the other Biochemistry 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.