Insulin Substrate Receptor (IRS) proteins in normal and malignant hematopoiesis

The insulin receptor substrate (IRS) proteins are a family of cytoplasmic proteins that integrate and coordinate the transmission of signals from the extracellular to the intracellular environment via transmembrane receptors, thus regulating cell growth, metabolism, survival and proliferation. The PI3K/AKT/mTOR and MAPK signaling pathways are the best-characterized downstream signaling pathways activated by IRS signaling (canonical pathways). However, novel signaling axes involving IRS proteins (noncanonical pathways) have recently been identified in solid tumor and hematologic neoplasm models. Insulin receptor substrate-1 (IRS1) and insulin receptor substrate-2 (IRS2) are the best-characterized IRS proteins in hematologic-related processes. IRS2 binds to important cellular receptors involved in normal hematopoiesis (EPOR, MPL and IGF1R). Moreover, the identification of IRS1/ABL1 and IRS2/JAK2V617F interactions and their functional consequences has opened a new frontier for investigating the roles of the IRS protein family in malignant hematopoiesis. Insulin receptor substrate-4 (IRS4) is absent in normal hematopoietic tissues but may be expressed under abnormal conditions. Moreover, insulin receptor substrate-5 (DOK4) and insulin receptor substrate-6 (DOK5) are linked to lymphocyte regulation. An improved understanding of the signaling pathways mediated by IRS proteins in hematopoiesis-related processes, along with the increased development of agonists and antagonists of these signaling axes, may generate new therapeutic approaches for hematological diseases. The scope of this review is to recapitulate and review the evidence for the functions of IRS proteins in normal and malignant hematopoiesis.

Adiposity in childhood cancer survivors: insights into obesity physiopathology / Adiposidade em pacientes tratados por câncer na infância: entendendo a fisiopatologia da obesidade

As childhood cancer treatment has become more effective, survival rates have improved, and a number of complications have been described while many of these patients reach adulthood. Obesity is a well-recognized late effect, and its metabolic effects may lead to cardiovascular disease. Currently, studies concerning overweight have focused on acute lymphocytic leukemia and brain tumors, since they are at risk for hypothalamic-pituitary axis damage secondary to cancer therapies (cranial irradiation, chemotherapy, and brain surgery) or to primary tumor location. Obesity and cancer have metabolic syndrome features in common. Thus, it remains controversial if overweight is a cause or consequence of cancer, and to date additional mechanisms involving adipose tissue and hypothalamic derangements have been considered, comprising premature adiposity rebound, hyperinsulinemia, leptin regulation, and the role of peroxisome proliferator-activated receptor γ. Overall, further research is still necessary to better understand the relationship between adipogenesis and hypothalamic control deregulation following cancer therapy.

Os avanços do tratamento contra o câncer infantil têm resultado no aumento da sobrevida e das complicações, à medida que os pacientes atingem a maioridade. A obesidade é um evento reconhecido, e seus efeitos metabólicos levam à doença cardiovascular. Atualmente, o estudo da obesidade tem enfocado a leucemia linfocítica aguda e os tumores cerebrais, já que ambos têm risco para lesões hipotalâmicas, secundárias às terapias (irradiação cranial, quimioterapia, e cirurgia) ou à localização do tumor. Obesidade e câncer têm em comum fatores para síndrome metabólica. Entretanto, a relação de causa e efeito entre obesidade e câncer permanece controversa, sendo que são considerados outros mecanismos envolvendo o tecido adiposo e lesões hipotalâmicas, como o rebote precoce de adiposidade, hiperinsulinemia, regulação da leptina, e o papel do receptor ativado por proliferadores de peroxissoma γ. Concluindo, mais estudos são necessários para entender a relação entre adipogênese e descontrole hipotalâmico em sobreviventes de câncer.

Leucemia de linfocitos grandes granulares: presentacion de un caso con escasa expresion en sangre periferica / Large granular lymphocytic leukemia: case report with scarce expression in peripheral blood

Una paciente de 33 años consultó por infecciones bacterianas reiteradas y granulocitopenia severa. El recuento absoluto de neutrófilos era 270/uL y el linfocitario 3000/uL, con 35 por ciento de linfocitos grandes granulares. El mielograma por punción aspirativa fue hipocelular, con disminución de elementos maduros mieloides y 50 por ciento de linfocitos. En la biopsia de médula ósea de observó un infiltrado linfoide nodular e intersticial y fibrosis reticulínica. Mediante inmunohistoquímica se demonstró fenotipo T supresor en la población linfoide de médula ósea, con lo cual se diagnosticó enfermedad linfoprofiferativa de linfocitos grandes granulares. Un estudio citogenético a partir del aspirado medular mostró la presencia del marcador 7q- en bajo porcentaje de las células, confirmando el origen clonal del cuadro. No hubo evidencia de rearreglo clonal en el estudio genético de cadena beta del receptor de linfocitos T. El suero de la paciente tuvo actividad inhibitoria sobre el crecimiento de colonias granulocito-macrofágicas autólogas y de donante normal. El tratamiento con pred-nisona en baja dosis permitió controlar la neutropenia.

Uso de sonda ventriculo-cerebral en el paciente con leucemia aguda / Use of intraventricular-cerebral catheter in a patient with acute leukemia

Enfermo masculino de 20 años de edad con diagn tico de Leucemia Aguda Linfoblastica (LAL), que durante el curso de su enfermedad a tenido una recaída a médula ósea y cinco a Sistema Nervicoso Central (SNC), además de infiltración ocular. Para sutratamiento se ha empleado la quimioterapia sistématica, quimioterapia intratecal (Qtx. IT) y radioterapia craneal (Rtx. C.). Se comenta en este paciente el uso de quimioterapia intraventricular, mediante la instalación de reservorio de Ommaya modificado en ventrículo lateral derecho. Este tipo de aditamentos pueden ser útiles en enfermos con LAL con factores de riesgo para infiltración a SNC .

Osteítis fibrosa quistica y síndrome hipercalcémico como manifestación inicial de leucemia lifoblástica / Osteitis fibrosa cystica and hypercalcemia syndrome as initial manifestatios of lymphoblastic leukemia

Se presenta el caso de un niño de 5 años, portador de una leucemia linfoblástica, que se manifestó inicialmente como un síndrome hipercalcémico y osteítis fibrosa quística. Se analizan los posibles mecanismos de producción de las lesiones óseas y de la hipercalcemia