1: Leuk Res. 2005 Oct 7; [Epub ahead of print] Histologic and molecular characterizations of megakaryocytic leukemia in mice. Hao X, Shin MS, Zhou JX, Lee CH, Qi CF, Naghashfar Z, Hartley JW, Fredrickson TN, Ward JM, Morse HC 3rd. Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institute of Health, Rockville, MD 20852, USA. Six cases of megakaryocytic leukemia (MKL) were identified and analyzed for morphology and molecular features. MKL were composed of megakaryocyte lineage cells ranging from immature to quite mature cells. VWF, GATA1 and RUNX1 were strongly expressed in megakaryocytes in both normal spleen and MKL as analyzed by immunohistochemistry (IHC). Altered expression of Meis1, Pbx1 and Psen2 and Lef1 in MKL detected with oligonucleotide microarrays was confirmed by qPCR and IHC. This is the first report of spontaneous MKL in mice, defining VWF as a biomarker for diagnosis and suggesting possible involvement of a series of genes in disease pathogenesis. PMID: 16219351 [PubMed - as supplied by publisher] --------------------------------------------------------------- 2: Leukemia. 2005 Jun;19(6):1042-50. Gene expression profiling of leukemic cell lines reveals conserved molecular signatures among subtypes with specific genetic aberrations. Andersson A, Eden P, Lindgren D, Nilsson J, Lassen C, Heldrup J, Fontes M, Borg A, Mitelman F, Johansson B, Hoglund M, Fioretos T. Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden. anna.andersson@klingen.lu.se Hematologic malignancies are characterized by fusion genes of biological/clinical importance. Immortalized cell lines with such aberrations are today widely used to model different aspects of leukemogenesis. Using cDNA microarrays, we determined the gene expression profiles of 40 cell lines as well as of primary leukemias harboring 11q23/MLL rearrangements, t(1;19)[TCF3/PBX1], t(12;21)[ETV6/RUNX1], t(8;21)[RUNX1/CBFA2T1], t(8;14)[IGH@/MYC], t(8;14)[TRA@/MYC], t(9;22)[BCR/ABL1], t(10;11)[PICALM/MLLT10], t(15;17)[PML/RARA], or inv(16)[CBFB/MYH11]. Unsupervised classification revealed that hematopoietic cell lines of diverse origin, but with the same primary genetic changes, segregated together, suggesting that pathogenetically important regulatory networks remain conserved despite numerous passages. Moreover, primary leukemias cosegregated with cell lines carrying identical genetic rearrangements, further supporting that critical regulatory pathways remain intact in hematopoietic cell lines. Transcriptional signatures correlating with clinical subtypes/primary genetic changes were identified and annotated based on their biological/molecular properties and chromosomal localization. Furthermore, the expression profile of tyrosine kinase-encoding genes was investigated, identifying several differentially expressed members, segregating with primary genetic changes, which may be targeted with tyrosine kinase inhibitors. The identified conserved signatures are likely to reflect regulatory networks of importance for the transforming abilities of the primary genetic changes and offer important pathogenetic insights as well as a number of targets for future rational drug design. PMID: 15843827 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 3: Blood. 1996 Jul 1;88(1):302-8. TEL-AML1 fusion RNA as a new target to detect minimal residual disease in pediatric B-cell precursor acute lymphoblastic leukemia. Cayuela JM, Baruchel A, Orange C, Madani A, Auclerc MF, Daniel MT, Schaison G, Sigaux F. Department of Clinical Hematology, Hopital Saint-Louis, Paris, France. It has recently been shown that the t(12;21)(p13;q22) translocation fuses two genes, TEL on chromosome 12 and AML1 on chromosome 21. We have evaluated the frequency of this newly described translocation in acute lymphoblastic leukemia (ALL), and the feasibility of minimal residual disease (MRD) monitoring by polymerase chain reaction (PCR) amplification of TEL-AML1 transcripts. Thirty-nine adult- and 45 childhood-ALLs consecutively diagnosed in a single center were included in this study. TEL-AML1 fusion transcripts were searched for in the 39 adult- and 45 childhood-ALLs for which material was available. BCR-ABL, E2A-PBX1, and MLL-AF4 transcripts were also studied by PCR in these cases. TEL-AML1 transcripts were found in 8 out of 35 (23%) childhood B-cell precursor ALLs (BCP-ALLs). TEL-AML1 transcripts were detected in only 1 of 31 adult BCP-ALLs (P = .04, Fisher's exact test). Nevertheless, in this adult case, TEL-AML1 transcripts were found at a low level in 2 of 3 different samples. BCR-ABL, E2A-PBX1, and MLL-AF4 transcripts were found in 12, 3, and 1 cases of 31 adult BCP-ALLs, and in 1, 2, and 1 cases of 35 childhood BCP-ALLs, respectively. TEL-AML1 transcripts were never found associated with any other fusion transcripts. Taken together, the four types of chimeric transcripts were detected in 12 of 35 (34%) childhood BCP-ALL cases. No TEL-AML1 transcripts were detected in 11 T-cell ALLs (4 adults and 5 children), nor in 2 B-cell (slg+) ALLs. MRD was evaluated in 21 samples collected in 9 TEL-AML1+ childhood BCP-ALL cases during therapy (median follow-up = 200 days). Of 8 patients evaluated after induction therapy, 4 showed detectable but low levels of MRD. Of 7 patients serially evaluated, only one showed persistence of detectable MRD. This study shows that TEL-AML1 transcripts are frequently detected in pediatric BCP-ALLs and that these transcripts are molecular targets that will simplify the strategy of MRD monitoring in childhood BCP-ALL. PMID: 8704188 [PubMed - indexed for MEDLINE] ---------------------------------------------------------------