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Spliceosome mutations in myeloid neoplasms

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. WHO classification of myeloid neoplasms. Myeloproliferative neoplasms

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Spliceosome mutations in myeloid neoplasms

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

  4. Outcome of MDS according to WHO classification 943 MDS pts Cazzola. Haematologica. 2011 Mar;96(3):349-52.

  5. Diagnosis of MDSis currently reliant on bone marrow morphology and cytogenetics • Peripheral cytopenia • Dysplasia • Clonal cytogenetic abnormality

  6. Diagnosis of MDSis 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: - 2005: JAK2 (V617F) - 2008: WHO diagnostic criteria - 2010: safety & efficacy of ruxolitinib in PMF - 2012: 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 Cazzola et al. Blood. 2003 Mar 1;101(5):1996-2000 - Pellagatti et al. Blood. 2006 - Della Porta et al. Leukemia. 2006 Apr;20(4):549-55 - Malcovati et al. J Clin Oncol. 2005 Oct 20;23(30):7594-603 RARS RARS

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

  10. SF3B1 mutations are present in the dominant clone Papaemmanuil et al. N Engl J Med. 2011 Oct 13;365(15):1384-95

  11. 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 Decreased (or increased) transcription of normal pre-mRNA (co-transcriptional RNA splicing) Exon skipping Intron retention Cryptic splice site (truncated exon) Exon 1 Exon 2 Exon 3 Exon 1 Exon 3 Exon 1 Intron Exon 2 Exon 3 Stem cells Hematopoietic precursors Exon 1 Exon 2 Exon 3

  14. Clinical significance of SF3B1 mutations in MDS Malcovati et al. Blood. 2011 Dec 8;118(24):6239-46

  15. Clinical significance of SRSF2 mutations in MDS Thol et al. Blood. 2012 Apr 12;119(15):3578-84

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

  17. RARS-T: molecular basis Somatic mutation of SF3B1 determining mitochondrial iron overload, ineffective erythropoiesis and anemia Somatic mutation of JAK2 or MPL determining gain of signaling and thrombocytosis Normal hematopoietic cell Ring sideroblasts and ineffective erythropoiesis (myelodysplastic features of RARS) Ring sideroblasts and thrombocytosis (myelodysplastic & myeloproliferative features of RARS-T) Cazzola et al. Blood. 2013 Jan 10;121(2):260-9

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

  19. International Cancer Genome Consortium Chronic Myeloid Disorders Working Group Eva Hellstrom-Lindberg David Bowen Jaqueline Boultwood James S Wainscoat Andrea Pellagatti Mike Groves Anthony Green Carlo Cambacorti-Passerini Paresh Vyas Nick Cross Elli PapaemmanuilPeter CampbellMike Stratton Luca Malcovati Matteo Della PortaAnna GallìIlaria AmbaglioCristiana PascuttoMario Cazzola AGIMM – AIRC-Gruppo Italiano Malattie Mieloproliferative

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