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71 - Acute lymphoblastic leukemia (ALL)

from Part 3.6 - Molecular pathology: lymphoma and leukemia

Published online by Cambridge University Press:  05 February 2015

By
Ido Paz-Priel  and
Alan D. Friedman
Edited by
Edward P. Gelmann ,
Charles L. Sawyers  and
Frank J. Rauscher, III
Ido Paz-Priel
Affiliation:
Departments of Oncology and Pediatrics, Division of Pediatric Oncology, Johns Hopkins University, Baltimore, MD, USA
Alan D. Friedman
Affiliation:
Departments of Oncology and Pediatrics, Division of Pediatric Oncology, Johns Hopkins University, Baltimore, MD, USA
Edward P. Gelmann
Affiliation:
Columbia University, New York
Charles L. Sawyers
Affiliation:
Memorial Sloan-Kettering Cancer Center, New York
Frank J. Rauscher, III
Affiliation:
The Wistar Institute Cancer Centre, Philadelphia
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Summary

It is estimated that 5760 new cases of acute lymphoblastic leukemia (ALL) will be diagnosed in 2013 (including 3509 children younger than 20 years), and 1400 patients will die from this disease(1). Genetically, ALL is one of the better-characterized malignancies, and common recurrent abnormalities are recognized and integrated into the risk stratification.

BCR–ABL1

Approximately 20–30% of adult cases of ALL are associated with the reciprocal translocation t(9;22)(q34,q11), or Philadelphia chromosome (Ph; 2,3) This translocation results in a head-to-tail fusion of the ABL1 proto-oncogene on chromosome 9 to the 5ʹ half of the breakpoint cluster region (BCR) from chromosome 22. The resulting chimeric BCR–ABL1 gene is expressed as a 210 or 190 kDa protein. The p190 product is common in ALL, while the p210 is characteristic of chronic myeloid leukemia (4). The N-terminus of the ABL1 kinase is the “Cap” region, which binds to the kinase domain and keeps the Src-homology-2 (SH2) and SH3 autoinhibitory structure in place, thus displacing catalytic residues from the active site and diminishing ATP accessibility (i.e. “off state”; 5,6). In contrast, the chimeric BCR–ABL1 protein is a constitutive kinase that activates the RAS, PI3K/AKT, MEK/ERK, and c-Jun/N-terminal kinase (JNK) pathways, and up-regulates the anti-apoptotic Bcl-2 and Bcl-X, overall resulting in enhanced cell proliferation and survival (7–10).

Type
Chapter
Information
Molecular Oncology
Causes of Cancer and Targets for Treatment
 , pp. 777 - 785
Publisher: Cambridge University Press
Print publication year: 2013

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