Lineage switch from pro-B acute lymphoid leukemia to acute myeloid leukemia in a case with t(12;17)(p13;q11)/TAF15–ZNF384 rearrangement

Numerous cytogenetic translocations have a prognostic impact in patients with acute lymphoid leukemia (ALL). In childhood ALL, good and poor risk cytogenetic subgroups that are routinely used to stratify patients and to address them to diff erent therapeutic strategies have been identifi ed. In adult ALL, the role of cytogenetics in patient management has largely been based on the presence of the Philadelphia (Ph) chromosome that derives from t(9;22)(q34;q11.2). However, over the years a number of genetic aberrations have been identifi ed which are associated with diff erent risk groups; the adverse prognostic signifi cance of some recurrent translocations, such as t(4;11) and to a lesser extent t(1;19) in adult ALL, and their correlation with a distinct immunophenotype, are well known. Th e t(12;17)(p13;q11) translocation, fi rst described in 1992, has been recently characterized and associated with a subgroup of immature B-lineage ALL co-expressing myeloid antigens (CD13, CD33) [1 – 7]. Th is translocation rearranges the ZNF384 transcription factor, on chromosome 12, with TAF15 on chromosome 17; this leads to production of the ZNF384 – TAF15 fusion transcript [4,8]. We hereby report a case of ZNF384 – TAF15 positive pro-B cell ALL that, at second relapse, 26 months after diagnosis, switched to an acute myeloid leukemia (AML) with t(12;17) (p13;q11)/ ZNF384 – TAF15 translocation. In February 2003, a 25-year-old woman was referred to our institution because of mild pancytopenia and fl u-like illness. Th e characteristics at diagnosis are shown in Table I. Bone marrow examination showed the presence of 82% blasts with lymphoid morphology; an immunophenotypic characterization, performed by fl ow cytometry according to standard operating procedures [9], indicated a diagnosis of pro-B cell ALL. Conventional cytogenetics according to the International System for Human Cytogenetic Nomenclature (ISCN) [10] detected a normal karyotype, while molecular studies by reverse transcriptase-polymerase chain reaction (RT-PCR) failed to detect the most common ALL associated rearrangements (i.e. BCR/ABL , ALL1/AF4 , ALL1/AF10 , SET/CAN , E2A/PBX , TEL/AML1 , NUP98/RAP1GDS1 , SIL/ TAL1 ). A diagnostic rachicentesis ruled out an impairment of the central nervous system and computed tomography showed absence of extramedullary involvement. As in all young cases of acute leukemia at onset at our institution, the patient underwent human leukocyte antigen (HLA) typing, which failed to identify the presence of a sibling donor. Treatment was started according to the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) LAL 2000 protocol [11], and a complete remission (CR) was achieved in April 2003; after completing the induction treatment, the patient was considered as standard risk, and received consolidation and maintenance therapy according to the protocol. In June 2005, the patient presented a fi rst hematological relapse. A biologic reevaluation was performed. FACScan analysis confi rmed the same immunophenotype detected at onset of the disease; again, molecular analysis was negative for the most common ALL rearrangements. Conventional karyotypic analysis showed a t(12;17)(p13;q11) translocation, and fl uorescence in situ hybridization (FISH), performed with the locus specifi c TEL/AML1 translocation probe (Abbott Molecular, Des Plaines, IL), excluded the involvement of ETV6 . Th e diagnostic bone marrow sample was subsequently reexamined by FISH, but no translocation was detected. Th e patient started reinduction therapy with high dose cytarabine plus mitoxantrone and obtained a second CR, which was followed by consolidation therapy with vincristine, methotrexate and cytarabine, administered for three cycles, up to September 2005. At this time, a bone marrow aspirate showed a monocytic component (17%) of uncertain signifi cance; immunophenotying analysis revealed 9% of blast cells positive for myeloid antigens. We performed a bone marrow biopsy on the hypothesis of a focal monoblastic infi ltration, and the presence of 50 – 60% of monocytoid blasts showing a CD79a , PAX5 , NPM , CD68 , CD34 phenotype was documented by immunohistochemistry; a diagnosis of French – American – British (FAB) M5b acute monocytic leukemia was made. Th e biologic reevaluation showed persistence of the t(12;17)(p13;q11) translocation at conventional L eu k L ym ph om a D ow nl oa de d fr om in fo rm ah ea lth ca re .c om b y T he U ni ve rs ity o f M an ch es te r on 1 0/ 29 /1 4