The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia

International Scoring System for Evaluating Prognosis in Myelodysplastic Syndromes

Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level. To determine the mutational spectrum associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define clonality and clonal evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major clonal evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions.

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Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing

Epidermal growth factor receptor (EGFR) has been detected in the nucleus in many tissues and cell lines. However, the potential functions of nuclear EGFR have largely been overlooked. Here we demonstrate that nuclear EGFR is strongly correlated with highly proliferating activities of tissues. When EGFR was fused to the GAL4 DNA-binding domain, we found that the carboxy terminus of EGFR contained a strong transactivation domain. Moreover, the receptor complex bound and activated AT-rich consensus-sequence-dependent transcription, including the consensus site in cyclin D1 promoter. By using chromatin immunoprecipitation assays, we further demonstrated that nuclear EGFR associated with promoter region of cyclin D1 in vivo. EGFR might therefore function as a transcription factor to activate genes required for highly proliferating activities.

/pdf/nuclear-localization-of-egf-receptor-and-its-potential-new-2pnz8rwauf.pdf

Nuclear localization of EGF receptor and its potential new role as a transcription factor

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly upregulated in cancers such as in non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer Various mechanisms mediate the upregulation of EGFR activity, including common mutations and truncations to its extracellular domain, such as in the EGFRvIII truncations, as well as to its kinase domain, such as the L858R and T790M mutations, or the exon 19 truncation These EGFR aberrations over-activate downstream pro-oncogenic signaling pathways, including the RAS-RAF-MEK-ERK MAPK and AKT-PI3K-mTOR pathways These pathways then activate many biological outputs that are beneficial to cancer cell proliferation, including their chronic initiation and progression through the cell cycle Here, we review the molecular mechanisms that regulate EGFR signal transduction, including the EGFR structure and its mutations, ligand binding and EGFR dimerization, as well as the signaling pathways that lead to G1 cell cycle progression We focus on the induction of CYCLIN D expression, CDK4/6 activation, and the repression of cyclin-dependent kinase inhibitor proteins (CDKi) by EGFR signaling pathways We also discuss the successes and challenges of EGFR-targeted therapies, and the potential for their use in combination with CDK4/6 inhibitors

Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways.

Pediatric Myelodysplasia: A Study of 68 Children and a New Prognostic Scoring System

We have analysed the haematological parameters in 21 patients with Shwachman-Diamond syndrome (SDS) seen over a 25-year period at our institution. Neutropenia, although present in all patients, was intermittent in two-thirds, constant in the rest and was associated with impaired chemotaxis in all of those patients tested. Fetal haemoglobin (HbF) was elevated in 80% of the patients at some stage, and anaemia and thrombocytopenia was documented in 66% and 24% respectively. Bone marrow samples were taken in over half of the patients. Myelodysplastic syndrome (MDS) developed in seven (33%) patients, five of whom had acquired clonal structural chromosome abnormalities in their bone marrows. In five of the patients with MDS (24%) transformation to acute myeloid leukaemia occurred. Like other constitutional bone marrow failure syndromes. SDS has a predilection to leukaemic transformation hitherto assumed to be in the region of 5-10%. The data presented here suggest that this figure probably represents an underestimate. Shwachman-Diamond syndrome is an interesting model of leukaemia development and greater understanding of the clinical spectrum of this rare disorder should produce further insights into its pathobiology.

Haematological abnormalities in Shwachman-Diamond syndrome

1. A series of experiments on the tensile strength of the anterior capsular mechanism have been performed. These show that in the young the weakest point is the glenoid labral attachment, whereas in the elderly calcification of tissues makes the capsule and subscapular tendon weaker. 2. It has been shown previously that glenoid labral detachment is the common injury in the young at the time of an acute dislocation, whereas capsular rupture and subscapularis tendon damage occur in the elderly. 3. These findings suggest that in an acute anterior dislocation of the shoulder the shoulder integuments give at their weakest point, and that it is the site of this weakest point and not the mechanism of injury which influences the liability to recurrence.

Experiments on the tensile strength of the anterior capsular structures of the shoulder in man.

We have analysed the prognostic influence of cytogenetic findings at diagnosis in a group of 502 children with acute lymphoblastic leukaemia (ALL), treated on MRC UKALL X, in whom clonal cytogenetic abnormalities were detected at diagnosis. Despite the overall improvement in outcome in children treated on this protocol compared with previous trials, some cytogenetically-defined groups were still associated with a poor outcome and ploidy retained some prognostic significance. Patients with high hyperdiploid ALL (39% of those with clonal abnormalities) had a favourable outcome with event free survival of 71% at 5 years. Those with near haploidy (1%), hypodiploidy (9%) and low hyperdiploidy (16.5%) had a relatively poor prognosis with event-free survival at 5 years of 17%, 42% and 49% respectively. Only two of 12 children with Ph-positive leukaemia are alive in remission and abnormalities of chromosome 11q23 were also associated with a high risk of treatment failure. In contrast, the t(1;19) was associated with improved event-free survival of 87.5% at 5 years. A number of other non-random abnormalities were identified with no clear prognostic significance. We conclude that identification of certain genetic changes remains important in the management of acute lymphoblastic leukaemia, although whether molecular diagnosis of clinically relevant abnormalities can now supplant cytogenetics in the clinical trials context remains to be determined.

Cytogenetics and prognosis in childhood lymphoblastic leukaemia: results of MRC UKALL X

1. Sacred beliefs and beliefs of sacredness Jane Hubert and Brian Reeves 2. Wintu sacred geography of northern California Dorothea J.Theodoratus & Frank LaPena 3. Sacred and secular neolithic landscapes in Ireland Gabriel Cooney 4. Sacred Space in the Culture of the Arctic Regions O. V. Ovsyannikov & N. M. Terebikhin 5. Sacred Sites in Madagascar Chantal Radimilahy 6. Places of Power: Mescalero Apache sacred sites and sensitive areas David L Carmichael 7. Sacred Sites in the Bamenda Grassfields of Cameroon: a study of sacred sites in the Nso' Fondom Mary Maimo Mumah 8. Bukusu sacred sites Simiyu Wandibba 9. Sacrificial places and their meaning in Saami society Inga-Maria Mulk 10. The Mijikenda Kaya as a sacred site Henry W. Mutoro 11. The perception and treatment of prehistoric and contemporary sacred places and sites in Poland Katarzyna Marciniak 12. Islam on the Kenyan Coast, faithful vs. unfaithful: an overview of Kenyan Coastal sacred sites George H.Abungu 13. A ceremony in a 'cave of idolatry': a document from the 18th century from the Archivo Historico Diocesano, Chiapas, Mexico Ines Sanmiguel 14. At the month of the obsidian cave: deity and place in Aztec religion Nick Saunders 15. Sto: Lo sacred ground Gordon Mohs 16. The spirits of the Chugach people of Alaska are at rest once again John F. C. Johnson 17. Maori sacred sites Mike Burns, Hirini Matunga & Alex Nathan 18. Principles and practice of site protection laws in Australia David Ritchie 19. When sacred land is sacred to three tribes: San Juan Paiute sacred sites and the Hopi-Navajo-Paiute Suit to Partition the 1934 Act Arizona Navajo Reservation Robert J. Franklin & Pamela A. Bunte 20. Tourism and the Bighorn Medicine Wheel: how multiple use does not work for sacred land sites Nicole Price 21. Ninastakis - the Nitsirapii's sacred mountain: traditional native religious activities and land use/tourism conflicts Brian Reeves

B. R. Reeves

Papers

Pediatric Myelodysplasia: A Study of 68 Children and a New Prognostic Scoring System

Haematological abnormalities in Shwachman-Diamond syndrome

Experiments on the tensile strength of the anterior capsular structures of the shoulder in man.

Cytogenetics and prognosis in childhood lymphoblastic leukaemia: results of MRC UKALL X

Sacred sites, sacred places