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Activating Mutations in JAK2 and Trisomy 21 Collaborate in Down Syndrome ALL

Fuerst, Mark

doi: 10.1097/01.COT.0000327558.28429.19

ATLANTA—The new discovery of a unique mutation in Down syndrome-related acute lymphoblastic leukemia (ALL) may allow clinicians to treat this condition with experimental kinase inhibitors. What's more, this specific association may reveal, in general, the genetic makeup of leukemias and help uncover associated mutations in other leukemias. So said Ithamar Ganmore, a medical student at Sheba Cancer Research Center in Ramat Gan, Israel, reporting the new data here at the American Society of Hematology Annual Meeting in a late-breaking session.

Patients with Down syndrome are at increased risk for both acute myeloid leukemia (AML) and ALL, and trisomy 21 (additional copies of chromosome 21) is a common genetic abnormality in both childhood leukemia and Down syndrome, he explained, noting that Down syndrome-related AML is uniquely characterized by an acquired mutation in the chromosome X gene GATA1. However, the existence of a similar unique mutation in Down syndrome-related ALL has not been seen before.

To identify such mutations, Dr. Ganmore and his colleagues performed a large mutational screen in 86 diagnostic samples of B-cell precursor Down syndrome ALL, stored in central labs of nine European childhood ALL protocols (representing more than 8,000 samples of childhood ALL).

“We found a JAK2 mutation in 16 [19%] of 86 Down syndrome ALL patients,” Mr. Ganmore said. “The mutations are different from those observed in myeloproliferative disorders.”

In all 16 patients a point mutation resulted in substitution of the conserved Arginine at position 683. There are five related Arg683-related mutations, and these mutations are unique to Down syndrome ALL, he said. “Only one mutation harbored the JAK2 R683 mutation. All patients had iso21q abnormality.”

Down syndrome ALL patients with mutated JAK2 are a distinct clinical subgroup—diagnosed at a younger age, with high white blood cell counts and JAK2 R683 mutations and other major chromosomal aberrations.”

The mutations cause constitutive activation of JAK2, and are predicted to disrupt a critical interaction between the pseudokinase and the SH2 domains. TEL-JAK2 and PCM1-JAK2 are involved in ALL as well as the JAKs involved in Down syndrome leukemias, Mr. Ganmore said.

“The mutations are acquired, as they do not exist in remission samples. The mutated RNA is expressed and activates JAK2. They are unique to Down syndrome ALL as screening of over 300 cases of non-Down syndrome ALL, as well as Down syndrome acute megakaryoblastic leukemia, has revealed only one instance with a similar mutation.” Strikingly, that patient had ALL with an iso21q abnormality, Mr. Ganmore said.

Speaking at a news conference at the meeting, the senior researcher for the study, Shai Izraeli, MD, Head of the Research Section of Pediatric Oncology at Sheba Cancer Research Center, explained that JAK2 is a tyrosine kinase that transmits proliferation signals from cytokines and growth factors, a mutation different from the one identified in polycythemia vera and other myeloproliferative syndromes. This suggests that specific mutations in JAK2 are involved in different subtypes of hematologic malignancies.

“Patients with Down syndrome have a higher risk of leukemia, ranging from 0.5 to 30 times more risk,” Dr. Izraeli said. “This tells us the extra chromosome 21 is leukomogenic. Somehow it causes leukemia, but only two percent of Down syndrome patients develop leukemia, so there must be an additional gene outside of chromosome 21 that leads to the development of leukemia.

“We found that a substantial proportion of patients with Down syndrome with leukemia have mutations in the JAK2 gene. This kinase is active in proliferation in cells, and over the last three years has been found in other proliferative disorders. It is acquired only in leukemia cells and is specifically associated with Down syndrome.”

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3 Important Implications

There are three important implications to the findings, Dr. Izraeli said. “Because of the wide involvement of JAK2, we may be able to treat Down syndrome ALL with new JAK2 inhibitors in clinical trials. Down syndrome patients may enjoy the benefit of new drugs in development.

Also, we found that the mutation in JAK2 is different from that in other myeloproliferative diseases. This tells us something about how JAK2 is involved in leukemogenesis. There may be different levels based on the area of JAK2 affected.

“And the data may be relevant not only to Down syndrome patients with leukemia. No single malignancy is caused by a single gene. This specific association may tell us something in general about leukemia and associated mutations in other leukemias.”

The data demonstrate that novel mutations of JAK2 cooperate with trisomy 21 in about 20% of cases of ALL in Down syndrome, Mr. Ganmore concluded. “Thus it seems that, like Down syndrome AML, about 20 percent of Down syndrome ALLs are different from sporadic childhood leukemias and characterized by unique acquired mutations in genes located outside chromosome 21—GATA1 on the chromosome X and JAK2 on chromosome 9.”

Beyond the obvious therapeutic implications, the observations raise the hypothesis that JAK2 is important in B-cell development and that constitutive activation of JAK2 in B-cell precursors provides a survival advantage in the presence of a germline trisomy 21, he added.

With this high frequency of JAK2 mutations in a group of patients, it may be useful to use JAK2 inhibitors in Down syndrome ALL, he said.

At the question-and-answer period after his presentation, Mr. Ganmore noted that all but one of the mutations were heterozygous. When asked whether the JAK2 mutation in Down syndrome was sufficient to cause ALL, he said that there might be other mutations involved as well.

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‘Drug Development Is Proceeding Along with the Biological Discoveries’

Richard A. Larson, MD, Professor and Director of Hematologic Malignancies at the University of Chicago Medical Center, commented in an interview after the news conference that the basis for this study on a biological level is who is at risk from more than one genetic hit.

“Clearly,” Dr. Larson said, “the Down syndrome patient population has a propensity to develop leukemia. Now an additional gene might participate in the generation of leukemia. Whether JAK2 inhibitors have a role in treatment is not clear. Preliminary data on JAK2 inhibitors is promising, and a number of drugs are in the pipeline.”

The other good news is that drug development is proceeding along with the biological discoveries, he said. “When we find a leukemia link like this, it's very exciting. BCR-ABL was discovered 50 years ago, but it took until Brian Druker's imatinib studies in the late 1990s to bring a therapy for chronic myelogenous leukemia into the clinic. It takes many years of basic science research to indicate a breakthrough drug like imatinib.”

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Genetic Disorder Doubles Risk for Lung Cancer

The genetic disorder of alpha-1 antitrypsin deficiency (αATD) doubles the risk of developing lung cancer in both smokers and nonsmokers, a study published in the Archives of Internal Medicine (2008;168:1097–1103) has reported.

Twelve researchers led by Ping Yang, MD, PhD, of the Division of Epidemiology at the Mayo Clinic, examined patients in three groups to determine whether αATD carriers are predisposed to a higher risk of lung cancer: 1,443 patients with lung cancer treated at the Mayo Clinic from 1997 to 2003; a control group of 797 residents in the community; and a second control group of 902 siblings of the lung cancer patients.

“αATD is a seriously underdiagnosed disorder, and people who have lung cancer and chronic obstructive pulmonary diseases in their families should be screened for these gene carriers.”

Among the patients with lung cancer, 13.4% were carriers of αATD, compared with 7.8% of the nonrelated controls. The estimated population attributable risk for αATD carriers was 11% for heavy smokers and 12% for never smokers, suggesting that the genetic disorder may explain a significant proportion of lung cancer in the general population, the authors wrote.

“This is a seriously underdiagnosed disorder and suggests that people who have lung cancer and chronic obstructive pulmonary diseases in their families should be screened for these gene carriers,” Dr. Ping said in a news release.

Although gene carriers were at a similarly greater risk for developing lung cancer regardless of smoking status (2.2-fold higher risk for never smokers, two-fold greater risk for light smokers and 2.3-fold increased risk for moderate to heavy smoker), a history of chronic obstructive pulmonary disease (COPD) translated into a six-fold increased risk for never smokers.

The next step is to further investigate whether the excess risk of lung cancer among patients with COPD is a result of lung tissue damage, airway obstruction, or both, the authors concluded.

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Adenovirus Vaccine for Prostate Cancer Shows Activity

A new prostate cancer vaccine may enable the immune system to fight the disease, researchers reported at the American Urological Association Annual Scientific Meeting. In a Phase I clinical trial (Abstract 526) reported by David M. Lubaroff, PhD, Director of Urology Research Laboratories and Professor of Urology and Microbiology at the University of Iowa, treated 32 men (median age of 71, median PSA of 128 ng/mL) with Stage D2 or D3 cancers with a single injection of adenovirus/PSA (Ad/PSA) vaccine at one to three dose levels. The patients were followed with physical and clinical chemistry exams at two and three weeks and two, four, eight, and 12 months.

Median follow-up was 12 months, and median survival was 18 months. At least 40% of patients developed immune responses to PSA, with anti-PSA antibodies produced in 42% of patients and anti-PSA T-cell responses in 71%. Over half of the patients (57%) survived longer than predicted, with doubling time increased in 48%. The longest survival was 71 months.

Although derived from a small number of patients, the data are encouraging enough to pursue further studies, the authors concluded, noting that a Phase II trial designed to expand these initial findings has recently been approved by the FDA.

© 2008 Lippincott Williams & Wilkins, Inc.
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