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Spliceosome mutations in myeloid neoplasms Mario Cazzola Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo Department of Molecular.

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Presentation on theme: "Spliceosome mutations in myeloid neoplasms Mario Cazzola Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo Department of Molecular."— Presentation transcript:

1 Spliceosome mutations in myeloid neoplasms Mario Cazzola Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo Department of Molecular Medicine, University of Pavia Pavia, Italy

2 WHO classification of myeloid neoplasms Myeloproliferative neoplasms Myelodysplastic syndromes Myelodysplastic/myeloproliferative neoplasms Acute myeloid leukemia

3 2008 WHO classification of MDS Progression to AML (25-30%) RCUD RARS RCMD RAEB-1 RAEB-2 MDS del(5q) Ineffective hematopoiesis Peripheral blood cytopenia Cazzola M. File image 2013

4 Outcome of MDS according to WHO classification Cazzola. Haematologica Mar;96(3): MDS pts

5 Diagnosis of MDS is currently reliant on bone marrow morphology and cytogenetics Peripheral cytopenia Dysplasia Clonal cytogenetic abnormality

6 Diagnosis of MDS is currently reliant on bone marrow morphology and cytogenetics Peripheral cytopenia Dysplasia Clonal cytogenetic abnormality lack of specificity poor inter-observer reliability

7 Clinical relevance of the molecular basis of disease Philadelphia-negative MPN: : JAK2 (V617F) : WHO diagnostic criteria : safety & efficacy of ruxolitinib in PMF : FDA & EMA approval of ruxolitinib for treatment of PMF

8 Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium Research project on the molecular basis of MDS started in 2010 with whole exome sequencing RARS Cazzola et al. Blood Mar 1;101(5): Pellagatti et al. Blood Della Porta et al. Leukemia Apr;20(4): Malcovati et al. J Clin Oncol Oct 20;23(30):

9 RNA splicing machinery RNA polymerase II DNA Spliceosome Pre-mRNA U1 U2 Cazzola M. File image 2013

10 SF3B1 mutations are present in the dominant clone Papaemmanuil et al. N Engl J Med Oct 13;365(15):

11 GeneFrequencyGeneFrequency SF3B1~25%STAG23% TET2~20%JAK2<5% SRSF2~10%MPL<5% RUNX1~10%ATRX<5% TP53<10%NPM1<5% ASXL1<10%IDH1- IDH2<5% NRAS/KRAS<10%NADPH<5% EZH2<10%CEBPA<5% CBL<10%CKIT<2% U2AF16%CSF1R<2% ZRSR23%PTPN11<2% BCOR3%GNAS<1% Mutant genes in MDS Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium, 2013

12 Targeted pathways in MDS Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium, 2013

13 Potential outcomes of spliceosome mutations Normal splicing Exon 1Exon 2Exon 3 Decreased (or increased) transcription of normal pre- mRNA (co-transcriptional RNA splicing) Exon skipping Exon 1Exon 3 Exon 1Exon 2Exon 3Intron Intron retention Cryptic splice site Exon 1Exon 3Exon 2 (truncated exon) Stem cellsHematopoietic precursors

14 Clinical significance of SF3B1 mutations in MDS Malcovati et al. Blood Dec 8;118(24):

15 Clinical significance of SRSF2 mutations in MDS Thol et al. Blood Apr 12;119(15):

16 Refractory anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T) as the paradigmatic example of MDS/MPN Anemia & thrombocytosis Ring sideroblasts (myelodysplastic feature) Abnormal megakaryocyte proliferation (myeloproliferative feature)

17 RARS-T: molecular basis Normal hematopoietic cell Ring sideroblasts and ineffective erythropoiesis (myelodysplastic features of RARS) Ring sideroblasts and thrombocytosis (myelodysplastic & myeloproliferative features of RARS-T) Somatic mutation of SF3B1 determining mitochondrial iron overload, ineffective erythropoiesis and anemia Somatic mutation of JAK2 or MPL determining gain of signaling and thrombocytosis Cazzola et al. Blood Jan 10;121(2):260-9

18 TET2 +/- SRSF2 & ASXL1 Courtesy of R. Solary

19 International Cancer Genome Consortium Chronic Myeloid Disorders Working Group Elli Papaemmanuil Peter Campbell Mike Stratton Luca Malcovati Matteo Della Porta Anna Gallì Ilaria Ambaglio Cristiana Pascutto Mario Cazzola Eva Hellstrom-Lindberg David Bowen Jaqueline Boultwood James S Wainscoat Andrea Pellagatti Mike Groves Anthony Green Carlo Cambacorti-Passerini Paresh Vyas Nick Cross AGIMM – AIRC-Gruppo Italiano Malattie Mieloproliferative


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