6 research outputs found
The role of the Janus-faced transcription factor PAX5-JAK2 in acute lymphoblastic leukemia
textabstractPAX5-JAK2 has recently been identified as a novel recurrent fusion gene in B-cell precursor acute lymphoblastic leukemia, but the function of the encoded chimeric protein has not yet been characterized in detail. Herein we show that the PAX5-JAK2 chimera, which consists of the DNA-binding paired domain of PAX5 and the active kinase domain of JAK2, is a nuclear protein that has the ability to bind to wild-type PAX5 target loci. Moreover, our data provide compelling evidence that PAX5-JAK2 functions as a nuclear catalytically active kinase that autophosphorylates and in turn phosphorylates and activates downstream signal transducers and activators of transcription (STATs) in an apparently noncanonical mode. The chimeric protein also enables cytokine-independent growth of Ba/F3 cells and therefore possesses transforming potential. Importantly, the kinase activity of PAX5-JAK2 can be efficiently blocked by JAK2 inhibitors, rendering it a potential target for therapeutic intervention. Together, our data show that PAX5-JAK2 simultaneously deregulates the PAX5 downstream transcriptional program and activates the Janus kinase-STAT signaling cascade and thus, by interfering with these two important pathways, may promote leukemogenesis
Copy Number Changes and Allele Distribution Patterns of Chromosome 21 in B Cell Precursor Acute Lymphoblastic Leukemia
Chromosome 21 is the most affected chromosome in childhood acute lymphoblastic leukemia. Many of its numerical and structural abnormalities define diagnostically and clinically important subgroups. To obtain an overview about their types and their approximate genetic subgroup-specific incidence and distribution, we performed cytogenetic, FISH and array analyses in a total of 578 ALL patients (including 26 with a constitutional trisomy 21). The latter is the preferred method to assess genome-wide large and fine-scale copy number abnormalities (CNA) together with their corresponding allele distribution patterns. We identified a total of 258 cases (49%) with chromosome 21-associated CNA, a number that is perhaps lower-than-expected because ETV6-RUNX1-positive cases (11%) were significantly underrepresented in this array-analyzed cohort. Our most interesting observations relate to hyperdiploid leukemias with tetra- and pentasomies of chromosome 21 that develop in constitutionally trisomic patients. Utilizing comparative short tandem repeat analyses, we were able to prove that switches in the array-derived allele patterns are in fact meiotic recombination sites, which only become evident in patients with inborn trisomies that result from a meiosis 1 error. The detailed analysis of such cases may eventually provide important clues about the respective maldistribution mechanisms and the operative relevance of chromosome 21-specific regions in hyperdiploid leukemias
Optical Genome Mapping Identifies Novel Recurrent Structural Alterations in Childhood ETV6::RUNX1+ and High Hyperdiploid Acute Lymphoblastic Leukemia
The mutational landscape of B-cell precursor acute lymphoblastic leukemia (BCP-ALL), the most common pediatric cancer, is not fully described partially because commonly applied short-read next generation sequencing has a limited ability to identify structural variations. By combining comprehensive analysis of structural variants (SVs), single-nucleotide variants (SNVs), and small insertions-deletions, new subtype-defining and therapeutic targets may be detected. We analyzed the landscape of somatic alterations in 60 pediatric patients diagnosed with the most common BCP-ALL subtypes, ETV6::RUNX1+ and classical hyperdiploid (HD), using conventional cytogenetics, single nucleotide polymorphism (SNP) array, whole exome sequencing (WES), and the novel optical genome mapping (OGM) technique. Ninety-five percent of SVs detected by cytogenetics and SNP-array were verified by OGM. OGM detected an additional 677 SVs not identified using the conventional methods, including (subclonal) IKZF1 deletions. Based on OGM, ETV6::RUNX1+ BCP-ALL harbored 2.7 times more SVs than HD BCP-ALL, mainly focal deletions. Besides SVs in known leukemia development genes (ETV6, PAX5, BTG1, CDKN2A), we identified 19 novel recurrently altered regions (in n ≥ 3) including 9p21.3 (FOCAD/HACD4), 8p11.21 (IKBKB), 1p34.3 (ZMYM1), 4q24 (MANBA), 8p23.1 (MSRA), and 10p14 (SFMBT2), as well as ETV6::RUNX1+ subtype-specific SVs (12p13.1 (GPRC5A), 12q24.21 (MED13L), 18q11.2 (MIB1), 20q11.22 (NCOA6)). We detected 3 novel fusion genes (SFMBT2::DGKD, PDS5B::STAG2, and TDRD5::LPCAT2), for which the sequence and expression were validated by long-read and whole transcriptome sequencing, respectively. OGM and WES identified double hits of SVs and SNVs (ETV6, BTG1, STAG2, MANBA, TBL1XR1, NSD2) in the same patient demonstrating the power of the combined approach to define the landscape of genomic alterations in BCP-ALL
CD371 cell surface expression: A unique feature of DUX4-rearranged acute lymphoblastic leukemia
none26noneSchinnerl, Dagmar; Mejstrikova, Ester; Schumich, Angela; Zaliova, Marketa; Fortschegger, Klaus; Nebral, Karin; Attarbaschi, Andishe; Fiser, Karel; Kauer, Maximilian O; Popitsch, Niko; Haslinger, Sabrina; Inthal, Andrea; Buldini, Barbara; Basso, Giuseppe; Bourquin, Jean-Pierre; Gaipa, Giuseppe; Brüggemann, Monika; Feuerstein, Tamar; Maurer-Granofszky, Margarita; Panzer-Grümayer, Renate; Trka, Jan; Mann, Georg; Haas, Oskar A; Hrusak, Ondrej; Dworzak, Michael N; Strehl, SabineSchinnerl, Dagmar; Mejstrikova, Ester; Schumich, Angela; Zaliova, Marketa; Fortschegger, Klaus; Nebral, Karin; Attarbaschi, Andishe; Fiser, Karel; Kauer, Maximilian O; Popitsch, Niko; Haslinger, Sabrina; Inthal, Andrea; Buldini, Barbara; Basso, Giuseppe; Bourquin, Jean-Pierre; Gaipa, Giuseppe; Brüggemann, Monika; Feuerstein, Tamar; Maurer-Granofszky, Margarita; Panzer-Grümayer, Renate; Trka, Jan; Mann, Georg; Haas, Oskar A; Hrusak, Ondrej; Dworzak, Michael N; Strehl, Sabin