These investigations and several others that have beenpublishedwithin recentyears compel us us to hold the view that the ratio of the vital capacity to the body length, trunk length, chest circumference,surfacearea or weight or any combination of thesemeasurements, is too variable to admit of any workable standardor normal value. On the other hand the vital capacity of each individual, after he had becomeaccustomedto the use of the spirometer,will be found to be subjectto but small variations as long as good health is maintained. Thereseems to beevidenceto show that a reductionin the vital capacityis ofen the first sign of a progressivedamageto the respiratorytissue.

The cancer cell

Described herein is a method of decreasing expression of HOXA1 in a subject having a cancer and/or myeloproliferative disorder associated with overexpression of a HOXA1 gene product where an effective amount of at least one miR-10a gene product or an isolated variant or biologically-active fragment thereof is administered to the subject sufficient to decrease expression of the HOXA1 gene product in the subject.

https://www.pnas.org/content/pnas/103/13/5078.full.pdf

MicroRNA fingerprints during human megakaryocytopoiesis

Gene expression profiling of pediatric acute myelogenous leukemia.

The mixed-lineage leukemia (MLL1/ALL-1/HRX) histone methyltransferase is involved in the epigenetic maintenance of transcriptional memory and the pathogenesis of human leukemias. To understand its role in cell type specification, we determined the human genomic binding sites of MLL1. We found that MLL1 functions as a human equivalent of yeast Set1. Like Set1, MLL1 localizes with RNA polymerase II (Pol II) to the 5′ end of actively transcribed genes, where histone H3 lysine 4 trimethylation occurs. Consistent with this global role in transcription, MLL1 also localizes to microRNA (miRNA) loci that are involved in leukemia and hematopoiesis. In contrast to the 5′ proximal binding behavior at most protein-coding genes, MLL1 occupies an extensive domain within a transcriptionally active region of the HoxA cluster. The ability of MLL1 to serve as a start site-specific global transcriptional regulator and to participate in larger chromatin domains at the Hox genes reveals dual roles for MLL1 in maintenance of cellular identity.

https://www.pnas.org/content/pnas/102/24/8603.full.pdf

Global and Hox-specific roles for the MLL1 methyltransferase.

The Mixed-lineage leukemia 1 (MLL1) gene (now renamed Lysine [K]-specific MethylTransferase 2A or KMT2A) on chromosome 11q23 is disrupted in a unique group of acute leukemias. More than 80 different partner genes in these fusions have been described, although the vast majority of leukemias result from MLL1 fusions with one of about six common partner genes. Approximately 10% of all leukemias harbor MLL1 translocations. Of these, two patient populations comprise the majority of cases: patients younger than one year of age at diagnosis (primarily acute lymphoblastic leukemias), and young- to-middle-aged adults (primarily acute myeloid leukemias). A much rarer subgroup of patients with MLL1 rearrangements develop leukemia that is attributable to prior treatment with certain chemotherapeutic agents – so-called “therapy related leukemias”. In general, outcomes for all of these patients remain poor when compared to patients with non-MLL1 rearranged leukemias. In this review we will discuss the normal biological roles of MLL1 and its fusion partners, how these roles are hypothesized to be dysregulated in the context of MLL1 rearrangements, and the clinical manifestations of this group of leukemias. We will go on to discuss the progress in clinical management and promising new avenues of research which may lead to more effective targeted therapies for affected patients.

/pdf/mll-rearranged-leukemias-an-update-on-science-and-clinical-2zml94plow.pdf

MLL-Rearranged Leukemias—An Update on Science and Clinical Approaches

The ALL-1 gene is directly involved in 5-10% of acute lymphoblastic leukemias (ALLs) and acute myeloid leukemias (AMLs) by fusion to other genes or through internal rearrangements. DNA microarrays were used to determine expression profiles of ALLs and AMLs with ALL-1 rearrangements. These profiles distinguish those tumors from other ALLs and AMLs. The expression patterns of ALL-1-associated tumors, in particular ALLs, involve oncogenes, tumor suppressors, antiapoptotic genes, drug-resistance genes, etc., and correlate with the aggressive nature of the tumors. The genes whose expression differentiates between ALLs with and without ALL-1 rearrangement were further divided into several groups, enabling separation of ALL-1-associated ALLs into two subclasses. One of the groups included 43 genes that exhibited expression profiles closely linked to ALLs with ALL-1 rearrangements. Further, there were evident differences between the expression profiles of AMLs in which ALL-1 had undergone fusion to other genes and AMLs with partial duplication of ALL-1. The extensive analysis described here pinpointed genes that might have a direct role in pathogenesis.

/pdf/expression-profiles-of-acute-lymphoblastic-and-myeloblastic-884rimvfpz.pdf

U. R. Kees

Papers

Expression profiles of acute lymphoblastic and myeloblastic leukemias with ALL-1 rearrangements