mercaptopurine and nelarabine

Topics: Adolescent; Adult; Aged; Allografts; Antigens, CD; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleosides; Asparaginase; Bone Marrow; Cell Lineage; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Doxorubicin; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunophenotyping; Male; Mercaptopurine; Methotrexate; Middle Aged; Mutation; Neoplasm Proteins; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prodrugs; Progression-Free Survival; Proportional Hazards Models; Retrospective Studies; Survival Rate; Vincristine; Young Adult

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleosides; Disease Progression; Fatal Outcome; Humans; Injections, Spinal; Male; Mediastinal Neoplasms; Mercaptopurine; Methotrexate; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Quadriplegia; Spinal Cord; Spinal Cord Diseases

Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric patients and over 50% of adult patients with ALL do not achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy the most substantial challenge in the treatment of this disease. Using whole-exome sequencing, we identify mutations in the cytosolic 5'-nucleotidase II gene (NT5C2), which encodes a 5'-nucleotidase enzyme that is responsible for the inactivation of nucleoside-analog chemotherapy drugs, in 20/103 (19%) relapse T cell ALLs and 1/35 (3%) relapse B-precursor ALLs. NT5C2 mutant proteins show increased nucleotidase activity in vitro and conferred resistance to chemotherapy with 6-mercaptopurine and 6-thioguanine when expressed in ALL lymphoblasts. These results support a prominent role for activating mutations in NT5C2 and increased nucleoside-analog metabolism in disease progression and chemotherapy resistance in ALL.

Topics: 5'-Nucleotidase; Antineoplastic Agents; Arabinonucleosides; Base Sequence; Cell Line; Drug Resistance, Neoplasm; HEK293 Cells; Humans; Mercaptopurine; Mutation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Sequence Analysis, DNA; Thioguanine

Topics: Adrenal Cortex Hormones; Adult; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleosides; Asparaginase; Bone Marrow Diseases; Diagnosis, Differential; Doxorubicin; Humans; Ischemia; Leukemic Infiltration; Male; Mercaptopurine; Methotrexate; Myelitis, Transverse; Paraplegia; Paresthesia; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Salvage Therapy; Spinal Cord; Vincristine