AML FLT3-ITD Internal Tandem Duplication MCQ — NEET PG Practice Question | NEETPGAI
AML FLT3-ITD Internal Tandem Duplication
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A 58-year-old man presents with newly diagnosed acute myeloid leukemia (AML) with a white blood cell count of 85,000/μL and 72% blasts on bone marrow examination. Cytogenetics shows a normal karyotype. Molecular testing reveals an internal tandem duplication (ITD) mutation in the gene located at the locus marked **A** (13q12.2). The allelic ratio of this mutation is 0.6. Which of the following best describes the pathogenic mechanism and prognostic significance of this mutation?
A. Loss-of-function mutation resulting in impaired hematopoietic progenitor cell proliferation and improved overall survival without targeted therapy
B. Point mutation in the tyrosine kinase domain causing intermediate-favorable prognosis and lower white blood cell counts at presentation
C. Ligand-dependent activation of JAK-STAT signaling with favorable prognosis in the setting of normal karyotype AML
D. Constitutive activation of STAT5, RAS-MAPK, and PI3K-AKT signaling with high allelic ratio conferring adverse prognosis per ELN 2022 risk stratification
Explanation
Why option 1 is correct
The structure at locus A (13q12.2) is the FLT3 gene, which encodes FMS-like tyrosine kinase 3, a class III receptor tyrosine kinase expressed on hematopoietic progenitor cells. Internal tandem duplications (FLT3-ITD) within the juxtamembrane domain cause ligand-independent constitutive dimerization and activation of downstream STAT5, RAS-MAPK, and PI3K-AKT signaling pathways, driving leukemic proliferation, impaired differentiation, and resistance to apoptosis. An allelic ratio ≥0.5 is classified as high and carries adverse prognosis according to the European LeukemiaNet (ELN) 2022 risk stratification, which is critical for treatment selection and transplant eligibility in first complete remission. This patient's allelic ratio of 0.6 places him in the adverse-risk category (NCCN Guidelines AML 2024).
Why each distractor is wrong
Option 2: FLT3-ITD mutations cause ligand-independent (constitutive) activation, not ligand-dependent activation. Additionally, normal karyotype AML with high allelic ratio FLT3-ITD is adverse-risk, not favorable-risk. This confuses the activation mechanism and misrepresents the prognostic impact.
Option 3: This describes FLT3-TKD (tyrosine kinase domain point mutations, most commonly D835), which account for 5–10% of FLT3 mutations and carry intermediate-favorable prognosis. FLT3-TKD is also associated with lower white blood cell counts. The clinical presentation here (high WBC, 72% blasts, ITD) is classic for FLT3-ITD, not FLT3-TKD.
Option 4: FLT3-ITD is a gain-of-function (activating) mutation, not a loss-of-function mutation. Loss-of-function would impair proliferation and would not drive the aggressive leukemic phenotype or require targeted therapy (midostaurin, gilteritinib). This is a fundamental mechanistic error.
High-YieldNEET PG
FLT3-ITD (~20–25% of AML) is constitutively active, high allelic ratio (≥0.5) is adverse-risk, and mandates midostaurin addition to 7+3 induction and allogeneic transplant in first CR.
