Individuals with neurofibromatosis type 1 (NF1) are predisposed to certain cancers including juvenile chronic myelogenous leukaemia (JCML). The NF1 tumour-suppressor gene encodes a protein (neurofibromin) that accelerates GTP hydrolysis on Ras proteins. Here we show that primary leukaemic cells from children with NF1 show a selective decrease in NF1-like GTPase activating protein (GAP) activity for Ras but retain normal cellular GAP activity. Leukaemic cells also show an elevated percentage of Ras in the GTP-bound conformation. JCML cells are hypersensitive to granulocyte-macrophage colony stimulating factor (GM-CSF), and we observed a similar pattern of aberrant growth in haematopoietic cells from Nf1-/- mouse embryos. These data define a specific role for neurofibromin in negatively regulating GM-CSF signaling through Ras in haematopoietic cells and they suggest that hypersensitivity to GM-CSF may be a primary event in the development of JCML.

IN OUR OPINION a comprehensive schema for descnption of the much discussed "total personality" is a pnme requirement in psydiology at this time The reasons for this need will be elaborated upon below, but may be stated bnefly as follows (1) Current conceptual systems in psychology usually emphasize only one of several areas of personality or one type of datum, e g, manifest or behavioral traits, central urges, psychodiagnostic categones, etc, and relationships among different areas and levels are but imperfectly dealt with, if at all (2) Most variables m current use in the field of psychology lack clear or systematic interpersonal reference(3) For the most part concepts oriented toward psycho-pathological functioning are emphasized, while those deahng with normal functioning are neglected (4) Many personality vanables in current use are not so stated or defined as to permit their objective measurementThis IS the first of a series of articles designed to present a comprehensive schema for the orgamzation of personality data The system to be described presents an account of the "total personality" based on a tripartite division of personahty data (le, the "total personality" is described by the nature of the data in each of three ' The studies on which this paper is based have been sponsored by Permanente Foundation Hospital, Oakland, California, under the codirection of Hubert S Coffey, Ph.D, and Harvey Powelson, M D The current expanded research pro}a:t >s in part supported by the U S Public Health Service under the direction of Saxton T Pope, Jr, M D The authors are grateful to Dr Jean Walker Macfarlane for her editorial contributions to this article A four-year collaborative research study involving 20Q subjects has provided the data aa which the theones of variables presented in this article are tased. For each subject there were available for study the protocols of ten personality tests and approximately cne thousand verbal interactions obtained by &e wire recording of group psychotherapy sessions.

Beginning chelation treatment with deferoxamine before the age of puberty can help children with transfusion-dependent thalassemia major to attain normal sexual maturation.

Deferoxamine is widely used therapeutically as a chelator of ferric ion in disorders of iron overload. This study demonstrates that this drug is a potent inhibitor of DNA synthesis by human B and T lymphocytes in vitro, but has relatively little effect on the synthesis of RNA and protein. The inhibitory effects of deferoxamine are completely reversible by washing or by adding stoichiometric amounts of Fe3+. Micromolar concentrations of deferoxamine decrease intracellular levels of deoxyribonucleoside triphosphates, which is similar to the effects of hydroxyurea. The binding of iron by deferoxamine likely causes an inhibition of ribonucleotide reductase activity, thereby preventing cells from completing the S phase of the cell proliferation cycle. As a reversible and nontoxic S-phase inhibitor, it may have important experimental and therapeutic applications.

A six week old infant with acute leukemia failed to attain remission with chemotherapy. Because we previously demonstrated that the iron chelator deferoxamine (DFO) has antiproliferative properties and modulatory effects on cell differentiation, a protocol was designed for in vitro study and for clinical use in the patient. At diagnosis, blast cells were morphologically undifferentiated, had nondiagnostic cytochemistry, showed an abnormal karyotype (t[4;11]), expressed markers of B cell lineage, and demonstrated C mu gene rearrangement. Tissue culture of marrow or blood cells yielded colonies of leukemic blasts. Increasing concentrations of DFO produced a dose-dependent suppression of patient's blast colony growth in vitro, and blasts within colonies showed a marked change in surface antigen expression from lymphoid to myelomonocytic markers, became monocytic in appearance, and developed intense staining for nonspecific esterase. When DFO was given intravenously to the patient as a single agent for 48 hours, blasts no longer expressed lymphoid antigens and became strongly positive for myelomonocytic markers, identical to the in vitro findings. Intravenous DFO halted rising peripheral blood blast cell numbers and allowed a several-fold increase in normal hematopoietic progenitor colony growth. When combined with low-dose cytosine arabinoside in the treatment protocol, DFO caused striking leukemic cytoreduction. Our findings indicate that DFO has antileukemic properties by virtue of its effects on proliferation and differentiation, and they prompt further experimental and clinical studies with this agent.