Activating CBL mutations are associated with a distinct MDS/MPN phenotype.

Activating point mutations in CBL have recently been identified in diverse subtypes of myeloid neoplasms. Because detailed clinical and hematological characteristics of CBL-mutated cases is lacking, we screened 156 BCR-ABL and JAK2 V617F negative patients with myeloproliferative neoplasms (MPN) and overlap syndromes between myelodysplastic syndrome (MDS) and MPN (MPS/MPN) for mutations in exons 8 and 9 of CBL by denaturing high-performance liquid chromatography and direct sequencing. CBL mutations were identified in 16/156 patients (10%), of which five also carried mutations in EZH2 (n = 3) and TET2 (n = 2). Comprehensive clinical and hematological characteristics were available from 13/16 patients (81%). In addition to splenomegaly (77%), striking common hematological features were CML-like left-shifted leukocytosis (85%) with monocytosis (85%), anemia (100%), and thrombocytopenia (62%). Thrombocytosis was not observed in any patient. Relevant bone marrow features (n = 12) included hypercellularity (92%) with marked granulopoiesis (92%), nonclustered microlobulated megakaryocytes (83%), and marrow fibrosis (83%). Nine deaths (progression to secondary acute myeloid leukemia/blast phase, n = 7; cytopenia complications, n = 2) were recorded. Three-year survival rate was 27%, possibly indicating poor prognosis of CBL mutated MDS/MPN patients.

Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms.

In a previous study, we identified somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in patients with myelodysplastic syndrome (MDS). Here, we define the clinical significance of these mutations in MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The coding exons of SF3B1 were screened using massively parallel pyrosequencing in patients with MDS, MDS/MPN, or acute myeloid leukemia (AML) evolving from MDS. Somatic mutations of SF3B1 were found in 150 of 533 (28.1%) patients with MDS, 16 of 83 (19.3%) with MDS/MPN, and 2 of 38 (5.3%) with AML. There was a significant association of SF3B1 mutations with the presence of ring sideroblasts (P < .001) and of mutant allele burden with their proportion (P = .002). The mutant gene had a positive predictive value for ring sideroblasts of 97.7% (95% confidence interval, 93.5%-99.5%). In multivariate analysis including established risk factors, SF3B1 mutations were found to be independently associated with better overall survival (hazard ratio = 0.15, P = .025) and lower risk of evolution into AML (hazard ratio = 0.33, P = .049). The close association between SF3B1 mutations and disease phenotype with ring sideroblasts across MDS and MDS/MPN is consistent with a causal relationship. Furthermore, SF3B1 mutations are independent predictors of favorable clinical outcome, and their incorporation into stratification systems might improve risk assessment in MDS.

PCM1-JAK2-fusion: a potential treatment target in myelodysplastic-myeloproliferative and other hemato-lymphoid neoplasms.

IMPORTANCE OF THE FIELD: Activating mutations of the JAK2 gene are of tumorigenic significance in myeloproliferative neoplasms. Translocations involving the JAK2 locus are of oncogenic importance in acute leukemias, myelodysplastic/myeloproliferative diseases and T-cell lymphomas. JAK2 locus gains, which are recurrent in Hodgkin's- and primary mediastinal B-cell lymphoma, are also efficient mechanisms of JAK2 activation. Recently, specific drugs blocking JAK2 have been developed and are currently in clinical trials. AREAS COVERED IN THIS REVIEW: We discuss possible mechanisms of deregulation and the significance of pericentriolar material 1 (PCM)1-JAK2 fusion/t(8;9)(p21-23;p23-24) in hematolymphoid neoplasms. Such cases show morphological (myeloproliferaton, eosinophilia, myelofibrosis) and clinical (striking male predominance, aggressive course) similarities. Since increased JAK2 oligomerization and tyrosine kinase domain activation is the probable oncogenic mechanism in this instance, such patients are promising candidates for JAK2 inhibitor therapy. WHAT THE READER WILL GAIN: The reader will gain important insights considering PCM1-JAK2 fusion in hematologic malignancies. TAKE HOME MESSAGE: JAK2 is a tyrosine kinase with oncogenic potential in hematologic malignancies. It can be activated by point mutations, translocations and amplifications. Beyond malignancies associated with JAK2 point mutations, those associated with translocations might be suitable for tyrosine kinase inhibitors, which merits prospective evaluation.

The molecular pathogenesis of myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) are frequently associated with clonally restricted cytogenetic abnormalities, but until recently, the molecular pathobiology underlying this diverse group of neoplastic bone marrow disorders has been largely obscure. During the last 10 years, many investigative groups have applied the formidable power of new molecular biology techniques to hunt for recurrent genetic alterations in MDS primary cells. Several genetic abnormalities, including mutations in RUNX1 (AML1), TET2, ASXL1 and TP53, have been discovered in a substantial fraction of MDS cases; genes rearranged or mutated less commonly in MDS include IER3, ATRX, RAS and FLT3. Furthermore, haploinsufficiency and expression changes in RPS14, miR-145 and miR-146a, CDC25c, PP2A and SPARC in the absence of point mutations have also been implicated in MDS pathobiology. A major challenge will be to determine which of these mutations are causative "drivers" either in the development or progression of MDS, which might be therapeutically important because they predict response to treatment, and which are merely "passengers" along for the ride that alter phenotype but have no effect on the natural history of the disease. While the altered cellular biology of MDS is also increasingly well-understood, many mysteries remain. Abnormalities in iron regulation, microenvironment interactions, regulation of apoptosis and oxidative damage/DNA repair may all play an important pathobiological role. By gaining a deeper understanding of the mechanisms of these complex and heterogeneous diseases, we will hopefully improve our ability to treat our patients with MDS beyond the therapies with limited effectiveness that are available at present.

[Myeloproliferative/myelodysplastic syndromes]. / Les syndromes myélodysplasiques-myéloprolifératifs.

Myeloproliferative/myelodysplastic syndromes are rare diseases that include a proliferative component, mainly on the white cells and platelets, and a dysplastic component that accounts for one or several cytopenias. The most frequent of these diseases in chronic myelo-monocytic leukemia, a disease of elderly people that has long been associated with myelodysplastic syndromes in biological studies as well as in clinical trials. The recent identification of a number of genetic mutations in the leukemic clone, including frequent mutations in TET2, ASXL1 and RUNX1, less frequent mutations in NRAS, KRAS and C-CBL, and rare mutations in JAK2, FLT3, IDH1, IDH2, and EZHR2 may improve our understanding of the pathogenesis of this disease. Patient care depends on the disease risk, especially the percentage of blast cells in the bone marrow, the age and the performance status. Supportive care is required in all patients. In high risk patients, the only curative therapeutic is allogeneic hematopoietic stem cell transplantation, which is rarely feasible due to the age of the patients and the absence of donor. Demethylating agents such as azacitidine and decitabine are currently the most efficient drugs. The prognosis remains poor, with a median survival lower than 24 months.