A 32-year-old man comes to the office due to progressive fatigue, easy bruising, and recurring episodes of gum bleeding. Physical examination shows several ecchymoses in his lower extremities. Laboratory studies are as follows: Bone marrow biopsy is performed and fluorescence in situ hybridization studies reveal a balanced translocation between the long arms of chromosomes 15 and 17. Which of the following proteins is most likely to be abnormal in the hematopoietic cells of this patient?

Question

A 32-year-old man comes to the office due to progressive fatigue, easy bruising, and recurring episodes of gum bleeding.  Physical examination shows several ecchymoses in his lower extremities.  Laboratory studies are as follows:  Bone marrow biopsy is performed and fluorescence in situ hybridization studies reveal a balanced translocation between the long arms of chromosomes 15 and 17.  Which of the following proteins is most likely to be abnormal in the hematopoietic cells of this patient?

Quizplus · Accepted Answer

Acute myelogenous leukemia (AML), characterized by failure of immature myeloid precursors (myeloblasts) to differentiate into mature granulocytes, is divided into 8 types (M0 through M7). Acute promyelocytic leukemia (APML), the M3 variant of AML, is associated with the t(15;17) cytogenetic translocation involving the promyelocytic leukemia (PML) gene on chromosome 15 and the retinoic acid receptor alpha (RARA) gene on chromosome 17. Fusion of these 2 genes produces PML/RARA, a chimeric gene (illustrated in this fluorescence in situ hybridization image) that codes for an abnormal retinoic acid receptor, which then inhibits myeloblast differentiation. Abnormal promyelocytes and Auer rods are seen on the smear. The clinical manifestations of AML, including anemia (fatigue, pallor), thrombocytopenia (petechiae, hemorrhages), and neutropenia (fever, opportunistic infections), result from marrow replacement by leukemic cells. As seen in this patient, APML is associated with disseminated intravascular coagulation (DIC), which is characterized by activation of the coagulation cascade. Laboratory findings seen in DIC include thrombocytopenia, elevated D-dimer due to fibrinolysis, and prolonged coagulation profile times (eg, prothrombin time, activated partial thromboplastin time) and low fibrinogen due to consumption. All-trans retinoic acid is used for treatment of APML. (Choice A) Mutations in the genes that code for the epidermal growth factor receptors are associated with certain lung (ERBB1), breast (ERBB2, also known as HER2/neu), ovarian, and gastric tumors. (Choice B) GTP-binding proteins are involved in cellular signal transduction. (Choice C) A defective platelet-derived growth factor receptor plays a role in the pathogenesis of several cancers, including ovarian cancers. (Choice D) An abnormal RB gene predisposes to development of retinoblastoma and osteosarcoma. Educational objective: The cytogenetic defect t(15;17) is associated with acute promyelocytic leukemia (APML). A translocation involving the retinoic acid receptor alpha (RARA) gene from chromosome 17 and the promyelocytic leukemia (PML) gene on chromosome 15 leads to the formation of PML/RARA, a fusion gene whose product inhibits differentiation of myeloblasts and triggers the development of APML.

A 32-Year-Old Man Comes to the Office Due to Progressive