A 41-year-old previously healthy woman comes to the office due to weakness and easy fatigability. She also has had several episodes of epistaxis and gum bleeding. Physical examination reveals mucosal pallor. Further evaluation demonstrates that the patient has a clonal proliferation of white blood cells containing an abnormal protein. In an experiment, the abnormal cells from the patient are purified and cultured in 2 different plates, one with a vitamin A derivative (plate 1) and the other with control (plate 2). After several days of incubation, cells in plate 1 are well differentiated compared to those in plate 2, and clonal proliferation is inhibited. This patient most likely has which of the following conditions?
Acute promyelocytic leukemia (APL), type M3 of acute myelogenous leukemia in the French-American-British classification system, results from a t(15;17) mutation whereby the gene for retinoic acid receptor alpha (RARα) is transferred from chromosome 17 to chromosome 15, where it fuses with the promyelocytic leukemia (PML) gene. This leads to the formation of a new gene called PML/RARα. Normally, RARα plays a role in the proper differentiation of myeloid precursors, as the receptor interacts with retinoic acid to affect transcription of genes required for maturation. However, the t(15;17) mutation in APML causes transcription repression and produces an abnormal receptor that is unable to signal for the differentiation of myeloid precursors at physiologic doses of retinoic acid.
Treatment with all-trans-retinoic acid (ATRA), a vitamin A derivative, overcomes this (partly by inducing PML/RARα proteolysis) and stimulates differentiation of myeloblasts into mature granulocytes. ATRA therapy induces remission in about 90% of patients with APL. APL is associated with disseminated intravascular coagulation.
(Choice A) Acute lymphocytic leukemia predominantly affects children. Blast cells positive for the CD10 antigen (CALLA) suggest a good prognosis.
(Choice C) Chronic lymphocytic leukemia is frequently seen in elderly patients. It presents with lymphadenopathy, hepatosplenomegaly, and anemia, and has an indolent course. Neoplastic cells resemble mature B lymphocytes.
(Choice D) In chronic myeloid leukemia (also commonly manifesting in elderly patients with fatigue, leukocytosis, and splenomegaly), myeloid precursors in different stages of differentiation proliferate. This disease is caused by a t(9;22) translocation that forms the BCR-ABL fusion gene, which codes for an abnormal tyrosine kinase.
(Choice E) Several high-grade non-Hodgkin lymphomas are associated with cytogenetic abnormalities. t(8;14), t(2;8), and t(8;22) are typical for Burkitt lymphoma; these translocations involve the c-myc oncogene. Burkitt lymphoma is associated with Epstein-Barr virus infection and classically has a "starry sky" histologic appearance.
Educational objective:
Acute promyelocytic leukemia is the M3 variant of acute myelogenous leukemia. It affects adult patients and may present with disseminated intravascular coagulation. The cytogenetic abnormality t(15;17) leads to formation of the promyelocytic leukemia-retinoic acid receptor alpha (PML/RARα) fusion gene, which is unable to signal for proper cellular differentiation, unlike the normal retinoic acid receptor.