Genetics of imatinib resistance in acute lymphoblastic leukemia

August 30, 2007

In the September 15th issue of Genes & Development, Drs. Richard T. Williams, Willem den Besten, and Charles J. Sherr at Howard Hughes Medical Institute, St. Jude Children’s Research Hospital in Memphis TN, lend new insights into how an aggressive form of acute lymphoblastic leukemia (ALL) develops, and how sensitivity to the targeted chemotherapeutic drug, imatinib, can be diminished through interactions between tumor cells and the host microenvironment.

ALL, a cancer of the bone marrow affecting 4,000 US residents annually, is characterized by the over-production of immature white blood cells. An aggressive form of ALL results from a chromosomal translocation, known as the Philadelphia chromosome (Ph), in which segments from chromosomes 9 and 22 are aberrantly fused together. Ph+ ALL is far more prevalent in adults (~30% of adult ALL) than in children (~4% of pediatric ALL), but it carries a poor prognosis in both age groups. Ph+ cells express a protein (encoded by an oncogene created by the chromosome fusion) called BCR-ABL. BCR-ABL is a constitutively active enzyme, a tyrosine kinase, which promotes uncontrolled cell proliferation.

Continuous treatment with the BCR-ABL tyrosine kinase inhibitor, imatinib, has revolutionized the therapy of another form of Ph+ cancer, chronic myelogenous leukemia (CML), by inducing durable remissions. However, the response of Ph+ ALL patients is not nearly as good, leading to shorter remissions and more rapid emergence of imatinib resistance. In general, Ph+ CML and ALL patients that fail imatinib therapy develop mutations in the BCR-ABL kinase that make them drug-resistant, but the reasons underlying the increased rate of emergence of mutant clones in Ph+ ALL has not been satisfactorily explained.

Williams and colleagues tracked the development of imatinib resistance, using a mouse model of Ph+ ALL. They engineered BCR-ABL-expressing lymphocyte progenitors that also lack the tumor suppressor protein ARF (which is deleted in more than 30% of Ph+ ALL patients, but not in CML patients, at their time of diagnosis). Interestingly, ARF-deficient lymphocytes expressing BCR-ABL were so highly aggressive that inoculation of as few as 20 such cells into healthy mice induced fatal ALL in less than 3 weeks. “Although experiments with CML support the concept that these leukemias arise from a rare population of ‘cancer stem cells’, our work on Ph+ ALL emphasizes that this need not be the case,” says Williams.

Further genetic experiments revealed that signals from the bone marrow micro-environment of the host animals were able to sustain the viability of ARF-deficient leukemia cells in the face of imatinib therapy. “We suspect that similar signals may nurture ARF-deficient Ph+ ALL cells in patients,” says Sherr, “thereby allowing the rapid emergence of imatinib-resistant clones.”

Source: Cold Spring Harbor Lab

Explore further: Proof-of principle study finds imatinib improves symptoms for patients with severe asthma

Related Stories

Proof-of principle study finds imatinib improves symptoms for patients with severe asthma

May 17, 2017
Mast cells, a type of white blood cell, are present in the airways of severe asthmatics even in the face of aggressive treatment, and their presence is associated with key indicators of severe asthma. It has long been thought ...

To beat leukemia, boost cell signaling, study suggests

March 26, 2015
A new study of acute lymphoblastic leukemia (ALL) led by UC San Francisco researchers puts an intriguing new twist on anti-cancer strategies. Rather than inhibiting cellular signals that arise from a cancer-driving gene—the ...

Prevalence of Ph-like ALL in adults underscores need for genetic testing, clinical trials

November 21, 2016
A high-risk subtype of acute lymphoblastic leukemia (ALL) first identified in children is highly prevalent in adults with ALL and is associated with a poor outcome, according to an international collaboration led by St. Jude ...

First comprehensive DNA study of mast cell leukemia uncovers clues that could improve therapy

December 16, 2011
Cancer researchers at Cold Spring Harbor Laboratory (CSHL) have carried out the first comprehensive study of the changes seen in the DNA of a patient with mast cell leukemia (MCL), an extremely aggressive subtype of acute ...

Options increase for CML patients failed by existing drugs

December 21, 2012
The U.S. Food and Drug Administration (FDA) this month expanded the options for patients with chronic myeloid leukemia and one form of acute lymphoblastic leukemia that carries the Philadelphia chromosome (Ph+ALL). It approved ...

Existing drugs offer new treatment options for high-risk childhood leukemia subtype

August 13, 2012
Scientists have identified new genetic alterations underlying a high-risk subtype of the most common childhood cancer that could be effectively targeted with existing leukemia therapies.

Recommended for you

Scientists provide insight into genetic basis of neuropsychiatric disorders

July 21, 2017
A study by scientists at the Children's Medical Center Research Institute at UT Southwestern (CRI) is providing insight into the genetic basis of neuropsychiatric disorders. In this research, the first mouse model of a mutation ...

Scientists identify new way cells turn off genes

July 19, 2017
Cells have more than one trick up their sleeve for controlling certain genes that regulate fetal growth and development.

South Asian genomes could be boon for disease research, scientists say

July 18, 2017
The Indian subcontinent's massive population is nearing 1.5 billion according to recent accounts. But that population is far from monolithic; it's made up of nearly 5,000 well-defined sub-groups, making the region one of ...

Mutant yeast reveals details of the aberrant genomic machinery of children's high-grade gliomas

July 18, 2017
St. Jude Children's Research Hospital biologists have used engineered yeast cells to discover how a mutation that is frequently found in pediatric brain tumor high-grade glioma triggers a cascade of genomic malfunctions.

Late-breaking mutations may play an important role in autism

July 17, 2017
A study of nearly 6,000 families, combining three genetic sequencing technologies, finds that mutations that occur after conception play an important role in autism. A team led by investigators at Boston Children's Hospital ...

Newly identified genetic marker may help detect high-risk flu patients

July 17, 2017
Researchers have discovered an inherited genetic variation that may help identify patients at elevated risk for severe, potentially fatal influenza infections. The scientists have also linked the gene variant to a mechanism ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.