A 35-year-old man presents with acute leukemia. Bone marrow examination reveals ≥20% blasts with both myeloid and monocytic differentiation, and notably, abnormal eosinophils with large basophilic granules and unsegmented nuclei. Cytogenetics shows the translocation marked **A** in the diagram. Which of the following best explains the pathogenic mechanism of this translocation and its clinical consequence?

Question

Accepted Answer

C. The CBFB-MYH11 fusion sequesters RUNX1 in the cytoplasm, acting as a dominant-negative inhibitor and blocking myelomonocytic differentiation. ## Why "The CBFB-MYH11 fusion sequesters RUNX1 in the cytoplasm, acting as a dominant-negative inhibitor and blocking myelomonocytic differentiation" is right

The inv(16)(p13.1q22) translocation marked **A** creates the CBFB-MYH11 fusion gene. CBFB normally encodes the beta subunit of core-binding factor that dimerizes with RUNX1 to enable normal myelomonocytic differentiation. When CBFB fuses with MYH11 (smooth muscle myosin heavy chain), the resulting fusion protein sequesters RUNX1 in the cytoplasm, preventing its nuclear translocation and function. This acts as a dominant-negative inhibitor, blocking differentiation and defining AML-M4Eo (acute myelomonocytic leukemia with abnormal eosinophils). This is a core-binding factor (CBF) AML with favorable prognosis (5-year OS 55–65%) despite the monocytic phenotype (Robbins 10e; NCCN AML 2024).

## Why each distractor is wrong

- **"The RUNX1-RUNX1T1 fusion prevents normal transcription factor function, leading to impaired granulocytic maturation"**: This describes t(8;21), marked **B** in the diagram, not inv(16). While t(8;21) is also a CBF AML with favorable prognosis, it is a different translocation and does not produce the characteristic abnormal eosinophils of AML-M4Eo.

- **"The PML-RARA fusion creates a constitutively active retinoic acid receptor, driving uncontrolled proliferation"**: This describes t(15;17), marked **C** in the diagram, which defines acute promyelocytic leukemia (APL). PML-RARA is a different fusion gene with distinct pathogenesis and clinical features (DIC, response to ATRA/arsenic).

- **"The BCR-ABL fusion produces a constitutively active tyrosine kinase that promotes proliferation in chronic myeloid leukemia"**: This describes t(9;22), marked **D** in the diagram, which is the hallmark of chronic myeloid leukemia (CML), not acute myeloid leukemia. BCR-ABL is a different fusion gene entirely.

**High-Yield:** inv(16) → CBFB-MYH11 → cytoplasmic sequestration of RUNX1 → blocked differentiation → AML-M4Eo with abnormal eosinophils and favorable prognosis; requires HiDAC consolidation and intrathecal prophylaxis for CNS relapse prevention.

[cite: Robbins 10e; NCCN AML 2024]

Answer

A. The RUNX1-RUNX1T1 fusion prevents normal transcription factor function, leading to impaired granulocytic maturation

Answer

B. The PML-RARA fusion creates a constitutively active retinoic acid receptor, driving uncontrolled proliferation

Answer

D. The BCR-ABL fusion produces a constitutively active tyrosine kinase that promotes proliferation in chronic myeloid leukemia

Explanation

Why "The CBFB-MYH11 fusion sequesters RUNX1 in the cytoplasm, acting as a dominant-negative inhibitor and blocking myelomonocytic differentiation" is right

Why each distractor is wrong

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