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Heterogeneous leukemia stem cells in myeloid blast phase chronic myeloid leukemia.
Chronic myeloid leukemia (CML) is an excellent model of the multistep processes in cancer. Initiating BCR-ABL mutations are required for the initial phase of the disease (chronic phase, CP-CML). Some CP-CML patients acquire additional mutation(s) that transforms CP-CML to poor prognosis, hard to treat, acute myeloid or lymphoid leukemia or blast phase CML (BP-CML). It is unclear where in the hemopoietic hierarchy additional mutations are acquired in BP-CML, how the hemopoietic hierarchy is altered as a consequence, and the cellular identity of the resulting leukemia-propagating stem cell (LSC) populations. Here, we show that myeloid BP-CML is associated with expanded populations that have the immunophenotype of normal progenitor populations that vary between patients. Serial transplantation in immunodeficient mice demonstrated functional LSCs reside in multiple populations with the immunophenotype of normal progenitor as well as stem cells. Multicolor fluorescence in situ hybridization detected serial acquisition of cytogenetic abnormalities of chromosome 17, associated with transformation to BP-CML, that is detected with equal frequency in all functional LSC compartments. New effective myeloid BP-CML therapies will likely have to target all these LSC populations.
Alternative agents versus prophylactic platelet transfusion for preventing bleeding in patients with thrombocytopenia due to chronic bone marrow failure: a network meta-analysis and systematic review.
This is the protocol for a review and there is no abstract. The objectives are as follows: To compare the relative efficacy of different treatments for thrombocytopenia (artificial platelet substitutes, platelet-poor plasma, fibrinogen, rFVIIa, rFXIII, thrombopoietin mimetics, antifibrinolytic drugs or platelet transfusions) in patients with chronic bone marrow failure and to derive a hierarchy of potential alternate treatments to platelet transfusions.
Analysis of GATA1 mutations in Down syndrome transient myeloproliferative disorder and myeloid leukemia.
Children with Down syndrome (DS) up to the age of 4 years are at a 150-fold excess risk of developing myeloid leukemia (ML-DS). Approximately 4%-5% of newborns with DS develop transient myeloproliferative disorder (TMD). Blast cell structure and immunophenotype are similar in TMD and ML-DS. A mutation in the hematopoietic transcription factor GATA1 is present in almost all cases. Here, we show that simple techniques detect GATA1 mutations in the largest series of TMD (n = 134; 88%) and ML-DS (n = 103; 85%) cases tested. Furthermore, no significant difference in the mutational spectrum between the 2 disorders was seen. Thus, the type of GATA1 sequence mutation is not a reliable tool and is not prognostic of which patients with TMD are probable to develop ML-DS.
Mrvi1, a common MRV integration site in BXH2 myeloid leukemias, encodes a protein with homology to a lymphoid-restricted membrane protein Jaw1.
Ecotropic MuLVs induce myeloid leukemia in BXH2 mice by insertional mutagenesis of cellular proto-oncogenes or tumor suppressor genes. Disease genes can thus be identified by viral tagging as common sites of viral integration in BXH2 leukemias. Previous studies showed that a frequent common integration site in BXH2 leukemias is the Nf1 tumor suppressor gene. Unexpectedly, about half of the viral integrations at Nf1 represented a previously undiscovered defective nonecotropic virus, termed MRV. Because other common integration sites in BXH2 leukemias encoding proto-oncogenes contain ecotropic rather than MRV viruses, it has been speculated that MRV viruses may selectively target tumor suppressor genes. To determine if this were the case, 21 MRV-positive BXH2 leukemias were screened for new MRV common integration sites. One new site, Mrvi1 was identified that was disrupted by MRV in two of the leukemias. Ecotropic virus did not disrupt Mrvi1 in 205 ecotropic virus-positive leukemias, suggesting that Mrvi1 is specifically targeted by MRV. Mrvi1 encodes a novel protein with homology to Jaw1, a lymphoid restricted type II membrane protein that localizes to the endoplasmic reticulum. MRV integration occurs at the 5' end of the gene between two differentially used promoters. Within hematopoietic cells, Mrvi1 expression is restricted to megakaryocytes and some myeloid leukemias. Like Jaw1, which is down-regulated during lymphoid differentiation, Mrv1 is downregulated during monocytic differentiation of BXH2 leukemias. Taken together, these data suggest that MRV integration at Mrvi1 induces myeloid leukemia by altering the expression of a gene important for myeloid cell growth and/or differentiation. Experiments are in progress to test whether Mrvi1 is a tumor suppressor gene.
Clinical and biological implications of driver mutations in myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic hematological malignancies characterized by dysplasia, ineffective hematopoiesis and a variable risk of progression to acute myeloid leukemia. Sequencing of MDS genomes has identified mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation, and cell signaling. We sequenced 111 genes across 738 patients with MDS or closely related neoplasms (including chronic myelomonocytic leukemia and MDS-myeloproliferative neoplasms) to explore the role of acquired mutations in MDS biology and clinical phenotype. Seventy-eight percent of patients had 1 or more oncogenic mutations. We identify complex patterns of pairwise association between genes, indicative of epistatic interactions involving components of the spliceosome machinery and epigenetic modifiers. Coupled with inferences on subclonal mutations, these data suggest a hypothesis of genetic "predestination," in which early driver mutations, typically affecting genes involved in RNA splicing, dictate future trajectories of disease evolution with distinct clinical phenotypes. Driver mutations had equivalent prognostic significance, whether clonal or subclonal, and leukemia-free survival deteriorated steadily as numbers of driver mutations increased. Thus, analysis of oncogenic mutations in large, well-characterized cohorts of patients illustrates the interconnections between the cancer genome and disease biology, with considerable potential for clinical application.