A 32-year-old woman presents with 10 days of fatigue, mucosal bleeding from gums, easy bruising, and heavy menstrual flow. Examination reveals scattered petechiae and gingival ooze. Labs show Hb 7.2 g/dL, platelets 18 ×10⁹/L, WBC 1.6 ×10⁹/L, prolonged PT/aPTT, fibrinogen 80 mg/dL, and markedly elevated D-dimer. Bone marrow aspirate is hypercellular with abnormal promyelocytes bearing butterfly-shaped nuclei, abundant azurophilic granules, and bundles of Auer rods (faggot cells). Cytochemistry shows MPO strongly positive (90%), and flow cytometry is CD13+, CD33+, CD117+, MPO+, HLA-DR negative, CD34 negative. The cytogenetic finding shown in the structure marked **B** in the diagram is most consistent with which molecular lesion?

Question

A 32-year-old woman presents with 10 days of fatigue, mucosal bleeding from gums, easy bruising, and heavy menstrual flow. Examination reveals scattered petechiae and gingival ooze. Labs show Hb 7.2 g/dL, platelets 18 ×10⁹/L, WBC 1.6 ×10⁹/L, prolonged PT/aPTT, fibrinogen 80 mg/dL, and markedly elevated D-dimer. Bone marrow aspirate is hypercellular with abnormal promyelocytes bearing butterfly-shaped nuclei, abundant azurophilic granules, and bundles of Auer rods (faggot cells). Cytochemistry shows MPO strongly positive (>90%), and flow cytometry is CD13+, CD33+, CD117+, MPO+, HLA-DR negative, CD34 negative. The cytogenetic finding shown in the structure marked **B** in the diagram is most consistent with which molecular lesion?

Accepted Answer

B. t(15;17)(q24;q21) producing PML-RARA fusion gene. ## Why t(15;17)(q24;q21) producing PML-RARA fusion gene is right

The morphologic hallmark of acute promyelocytic leukemia (APL, AML-M3) is the presence of faggot cells—bundles of multiple Auer rods within a single promyelocyte—combined with a characteristic coagulopathy (DIC with hyperfibrinogenolysis). The structure marked **B** in the diagram depicts these faggot cells with abundant azurophilic granules and bilobed nuclei. The defining molecular lesion of APL is the t(15;17) translocation, which fuses the PML gene on chromosome 15 with the RARA (retinoic acid receptor alpha) gene on chromosome 17. This PML-RARA fusion is required for diagnosis per WHO 2022, irrespective of morphology, and is the molecular basis for APL's unique responsiveness to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO).

## Why each distractor is wrong

- **t(8;21)(q22;q22) producing RUNX1-RUNX1T1 fusion gene**: This is the hallmark of AML-M2 (acute myeloblastic leukemia with maturation), which typically presents with single Auer rods, not faggot cells, and does not cause the severe coagulopathy characteristic of APL. This corresponds to structure **A** in the diagram.
- **inv(16)(p13q22) producing CBFB-MYH11 fusion gene**: This is another core binding factor AML (AML-M4Eo with eosinophilia) that presents with monocytic differentiation and eosinophilic abnormalities, not the pure promyelocytic morphology with faggot cells shown in **B**.
- **t(9;11)(p21;q23) producing KMT2A-MLLT3 fusion gene**: This translocation is associated with AML-M5 (acute monocytic/monoblastic leukemia), which presents with monoblasts bearing cup-shaped nuclei and lacks the characteristic Auer rod bundles and coagulopathy of APL. This corresponds to structure **C** in the diagram.

**High-Yield:** APL (AML-M3) is the ONLY AML subtype defined by a single recurrent translocation (t(15;17)/PML-RARA) that is mandatory for diagnosis and is uniquely curable with ATRA + ATO, not chemotherapy.

[cite: WHO 2022 Classification of Haematolymphoid Tumours; Lo-Coco et al. APML4 trial; Sanz & Lo-Coco, Blood 2021]

Answer

A. inv(16)(p13q22) producing CBFB-MYH11 fusion gene

Answer

C. t(8;21)(q22;q22) producing RUNX1-RUNX1T1 fusion gene

Answer

D. t(9;11)(p21;q23) producing KMT2A-MLLT3 fusion gene

Explanation

Why t(15;17)(q24;q21) producing PML-RARA fusion gene is right

Why each distractor is wrong

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