Leukemia (1999) 13, 2007–2011  1999 Stockton Press All rights reserved 0887-6924/99 $15.00 http://www.stockton-press.co.uk/leu Pre-B acute lymphoblastic leukemia with b3a2 (p210) and e1a2 (p190) BCR-ABL fusion transcripts relapsing as chronic myelogenous leukemia with a less differentiated b3a2 (p210) clone SS Winter 1 , JM Greene 2 , TS McConnell 3 and CL Willman 3 Departments of 1 Pediatrics, Division of Oncology, 3 Pathology, 2 School of Medicine, Center for Molecular and Cellular Diagnostics, The University of New Mexico Health Sciences Center and Cancer Center, Albuquerque, New Mexico 87131, USA The Philadelphia chromosome translocation t(9;22)(q34;q11) may give rise to different BCR/ABL fusion mRNAs due to differ- ent genomic breakpoints and alternative splicing. The e1a2, b2a2 or b3a2 and c3a2 fusion mRNAs encode distinct fusion proteins (p190, p210 and p230, respectively), which are asso- ciated with different forms of leukemogenesis in humans and animal models. Our patient presented with acute pre-B cell lym- phoblastic leukemia (ALL) with normal cytogenetics. After 3 years of standard ALL therapy, he relapsed with t(9;22)-positive chronic myelogenous leukemia (CML). Retrospective molecular analyses of the pre-treatment pre-B cell ALL sample showed the b3a2 (p210) and e1a2 (p190) BCR/ABL fusion transcripts. Only the b3a2 (p210) transcript was detected at relapse. South- ern and immunoglobulin heavy chain (IgH) analyses of the presentation and relapse samples revealed an identical BCR rearrangement in both samples. However, only the ALL sample harbored an IgH gene rearrangement. These findings show a clonal relationship between the more differentiated pre-B cell and less differentiated CML clones and that the p210 and p190 fusion mRNAs were alternatively spliced from a single genomic breakpoint. Our patient’s unusual molecular findings provide circumstantial evidence that the p190 protein may promote a more differentiated phenotype in a comparatively less differen- tiated p210-transformed precursor cell. Keywords: acute lymphoblastic leukemia; chronic myelogenous leukemia; Philadelphia chromosome; BCR/ABL; p210; p190 Introduction The Philadelphia chromosome (Ph1) is a balanced reciprocal translocation, t(9;22)(q34;q11.2), associated with chronic myelogenous leukemia (CML) and acute leukemias of the lymphoid and myeloid lineages. While the vast majority of patients with CML have an associated t(9;22), this translo- cation also occurs in 20–30% of adults and only 2–5% of children with acute lymphoblastic leukemia (ALL). 1,2 The t(9;22) results in the juxtaposition of the Abelson gene (ABL) on chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11 to yield a variety of BCR/ABL fusion transcripts. 3 Each of these BCR/ABL fusion transcript variants is associated with biologically and clinically distinct forms of leukemogenesis. The majority of patients with CML have BCR breakpoints involving two different exons (b2 or b3) in the 8.5 kb major breakpoint cluster (M-BCR). Fusion of either of these exons to ABL common exon II yields two distinct mRNA fusion transcripts (referred to as b2a2 or b3a2), each of which encode distinct p210BCR-ABL fusion proteins. More rarely, patients with CML may have BCR breakpoints outside the M-BCR cluster. Such variants include the e19a2 fusion (fusing BCR exons 1–19 to common exon II of ABL) encoding a p230BCR-ABL fusion protein associated with the chronic neutrophilic variant of CML, 4 the CML-associated Correspondence: SS Winter; Fax: 505 272 8699 Received 21 December 1998; accepted 13 August 1999 e6a2 BCR/ABL fusion mRNA encoding a protein slightly larger than 185 kDa, 5 and rare CML cases lacking ABL exon 2. 6 In contrast, the majority of children with Ph1-positive ALL, nearly 50% of adults with ALL, and rare CML pateints have a distinct set of BCR breakpoints within the large first BCR intron 1 (referred to as the minor breakpoint cluster region). Such genomic breakpoints lead to a distinct e1a2 BCR/ABL fusion from mRNA and a p190 fusion protein. 7 While all of the various BCR-ABL fusion mRNAs proteins share a relatively similar carboxy terminal ABL tyrosine kinase domain, they differ considerably in their BCR domains. Clearly, the various BCR/ABL fusion proteins contain a num- ber of moieties that mediate intracellular signalling events. The ABL carboxy terminal tyrosine domain, BCR SH2-binding domains and dbl-like domains are thought to play key roles in pluripotential cell transformation. 8,9 How the inclusion or exclusion of these various signalling moieties in the different BCR/ABL fusions promotes different forms of leukemogenesis is currently of great interest. In comparison to the p210BCR- ABL fusion which is associated with multilineage leukemo- genesis after a relatively long latency period in animal models, the p190BCR-ABL protein has been shown to be more actively transforming and appears to have an accelerated propensity for promoting more differentiated acute B cell lineage leuke- mias in two mouse models. 10,11 In humans, the p190BCR-ABL fusion has been associated with acute, more ‘differentiated’ and aggressive leukemias having either differentiated B cell or myeloid features. 12,13 We describe an adolescent male who first presented with acute pre-B cell ALL containing one BCR genomic rearrange- ment and two BCR/ABL fusion transcripts (b3a2 and e1a2) arising through alternative splicing. These more differentiated pre-B cells were also characterized by a clonal rearrangment of the immunoglobulin heavy (IgH) chain locus. Case report A 13-year-old white male presented with a 1-month history of fatigue, lethargy and weight loss. Physical examination was remarkable for pallor, lymphadenopathy and moderate hepa- tospenomegaly. The complete blood count showed a leuko- cyte count of 96.8 × 10 9 cells/l with 1% banded neutrophils, 12% lymphocytes and 87% blasts, a hemoglobin of 88 g/l, and a platelet count of 142 × 10 9 cells/l. The chest radiograph and cerebral spinal fluid were normal. His bone marrow was replaced with 95% blasts having FAB L1 morphology. The surface marker profile showed expression of CD10, CD19, CD20, CD34, CD38, HLA DR and cytoplasmic  (CD13 and CD33 were negative). Routine cytochemical stains for Tdt, myeloperoxidase, and Periodic Acid Schiff (PAS) were positive only for Tdt. The initial bone marrow karyotype from unstimu- lated cells showed 46,XY in 14 out of 20 metaphases without