MicroRNA characterize genetic diversity and drug resistance in pediatric acute lymphoblastic leukemia.
نویسندگان
چکیده
BACKGROUND MicroRNA regulate the activity of protein-coding genes including those involved in hematopoietic cancers. The aim of the current study was to explore which microRNA are unique for seven different subtypes of pediatric acute lymphoblastic leukemia. DESIGN AND METHODS Expression levels of 397 microRNA (including novel microRNA) were measured by quantitative real-time polymerase chain reaction in 81 cases of pediatric leukemia and 17 normal hematopoietic control cases. RESULTS All major subtypes of acute lymphoblastic leukemia, i.e. T-cell, MLL-rearranged, TEL-AML1-positive, E2A-PBX1-positive and hyperdiploid acute lymphoblastic leukemia, with the exception of BCR-ABL-positive and 'B-other' acute lymphoblastic leukemias (defined as precursor B-cell acute lymphoblastic leukemia not carrying the foregoing cytogenetic aberrations), were found to have unique microRNA-signatures that differed from each other and from those of healthy hematopoietic cells. Strikingly, the microRNA signature of TEL-AML1-positive and hyperdiploid cases partly overlapped, which may suggest a common underlying biology. Moreover, aberrant down-regulation of let-7b (~70-fold) in MLL-rearranged acute lymphoblastic leukemia was linked to up-regulation of oncoprotein c-Myc (P(FDR)<0.0001). Resistance to vincristine and daunorubicin was characterized by an approximately 20-fold up-regulation of miR-125b, miR-99a and miR-100 (P(FDR)≤0.002). No discriminative microRNA were found for prednisolone response and only one microRNA was linked to resistance to L-asparaginase. A combined expression profile based on 14 microRNA that were individually associated with prognosis, was highly predictive of clinical outcome in pediatric acute lymphoblastic leukemia (5-year disease-free survival of 89.4%±7% versus 60.8±12%, P=0.001). CONCLUSIONS Genetic subtypes and drug-resistant leukemic cells display characteristic microRNA signatures in pediatric acute lymphoblastic leukemia. Functional studies of discriminative and prognostically important microRNA may provide new insights into the biology of pediatric acute lymphoblastic leukemia.
منابع مشابه
NUDT15 genetic variants and 6-mercaptopurine intolerance in pediatric acute lymphoblastic leukemia: an updated review
Acute lymphoblastic leukemia (ALL) accounts for nearly 30% of pediatric cancers. The maintenance treatment for ALL comprises daily oral 6-mercaptopurine (6-MP) and weekly methotrexate (MTX). 6-MP is a purine analog that can significantly improve the long-term survival of ALL patients. Despite more than 90% of 5-year survival of childhood ALL in developed countries, treatment interruption due to...
متن کاملMicroRNAs as a New Molecular Biomarker for Diagnosis and Prognosis of T-cell Acute Lymphoblastic Leukemia (T-ALL): A Systematic Review
MicroRNAs (miRNAs, miRs) are small endogenous non-coding RNAs that regulate the expression of protein-encoding genes at the post-transcriptional level. Several studies have described the role of miRNAs in T-cell acute lymphoblastic leukemia (T-ALL), including tumor suppressor and oncogenic miRNAs. Down-regulation of miRNA expression is a prominent feature of human malignancy. This down-regulati...
متن کاملDiversity of T-cell receptor Gene Rearrangements in South Indian Patients with Common Acute Lymphoblastic Leukemia
Background: Precursor B-Acute Lymphoblastic Leukemia (precursor B-ALL) oc-curs due to the uncontrolled proliferation of B-lymphoid precursors arrested at a par-ticular stage of B-cell development. Precursor-B-ALL is classified mainly into pro-B-ALL, common-ALL and pre-B-ALL. The Common Acute Lymphoblastic Antigen CD10 is the marker for common-ALL. Objective: This study was aimed to examine the ...
متن کاملغربالگری فاکتورهای پیشآگهی دهنده با استفاده از تکنیک Multiplex RT-PCR در ردههای مختلف سلولهای لوسمی
Background: Leukemia is one of the most common pediatric malignancies. T-cell Acute Lymphoblastic Leukemia (T-ALL) accounts for 15% of hematopoetic cancers. It has been well understood that identification of genetic alterations associated with leukemias is very critical. The molecular genetic techniques have promoted the identification of leukemia-associated genetic changes that may characteriz...
متن کاملPolymorphisms within methotrexate pathway genes: Relationship between plasma methotrexate levels, toxicity experienced and outcome in pediatric acute lymphoblastic leukemia
Objective(s): The current study aimed to investigate the relationship of genetic polymorphism and plasma methotrexate (MTX) levels, toxicity experience and event free survival (EFS) in pediatric acute lymphoblastic leukemia (ALL). Materials and Methods: The study included 74 ALL patients. Polymerase chain reaction and genotyping of methy...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Haematologica
دوره 96 5 شماره
صفحات -
تاریخ انتشار 2011