A novel Monoclonal Antibody against Notch1 Targets Leukemia-associated Mutant Notch1 and Depletes Therapy Resistant Cancer Stem Cells in Solid Tumors.

Higher Notch signaling is known to be associated with hematological and solid cancers. We developed a potential immunotherapeutic monoclonal antibody (MAb) specific for the Negative Regulatory Region of Notch1 (NRR). The MAb604.107 exhibited higher affinity for the "Gain-of-function" mutants of Notch1 NRR associated with T Acute lymphoblastic Leukemia (T-ALL). Modeling of the mutant NRR with 12 amino-acid insertion demonstrated "opening" resulting in exposure of the S2-cleavage site leading to activated Notch1 signaling. The MAb, at low concentrations (1-2 µg/ml), inhibited elevated ligand-independent Notch1 signaling of NRR mutants, augmented effect of Thapsigargin, an inhibitor of mutant Notch1, but had no effect on the wild-type Notch1. The antibody decreased proliferation of the primary T-ALL cells and depleted leukemia initiating CD34/CD44 high population. At relatively high concentrations, (10-20 µg/ml), the MAb affected Notch1 signaling in the breast and colon cancer cell lines. The Notch-high cells sorted from solid-tumor cell lines exhibited characteristics of cancer stem cells, which were inhibited by the MAb. The antibody also increased the sensitivity to Doxorubucinirubicin. Further, the MAb impeded the growth of xenografts from breast and colon cancer cells potentiated regression of the tumors along with Doxorubucin. Thus, this antibody is potential immunotherapeutic tool for different cancers.

Accelerated phase of chediak higashi syndrome mimicking lymphoma--a case report.

SUMMARY: Chediak Higashi Syndrome (CHS) is a rare autosomal recessive disease, characterized by partial oculocutaneous albinism, frequent pyogenic infections, and the presence of abnormal large granules in leukocytes and other granule containing cells. The abnormal granules are readily seen in blood and marrow granulocytes. About 50% to 85% of patients eventually enter an accelerated phase, manifested by fever, lymphadenopathy, anemia, jaundice, neutropenia, thrombocytopenia, and widespread lymphohistiocytic organ infiltrates. The first accelerated phase of CHS may occur shortly after birth or several years later. Most patients undergo a variable period of recurrent infections before going into the accelerated phase. Therefore, primary presentation in the accelerated phase is unusual. This case was referred to our institution that is a tertiary care cancer centre, with a clinical diagnosis of lymphoma/leukemia. Hence this interesting case of CHS in accelerated phase at presentation is described. The child had 1-month history of fever, bilateral neck swellings, and loss of appetite. On the basis of the clinical presentation, hematologic, and histopathologic findings, a diagnosis of accelerated phase of CHS was made. The child was treated with antipyretics, antibiotics, and stem cell transplantation was suggested to him. When the child presents to a hospital with oculocutaneous albinism and recurrent infections, careful examination of the peripheral blood smear by an experienced morphologist cannot be overemphasized. A high degree of awareness and early recognition of the syndrome, could lead to the institution of the only possible curative treatment, bone marrow transplant, before the accelerated phase supervenes.