Jak of all trades? Not of leukaemia therapy
About one in five or six cases of adult leukaemia in Western populations relates to so-called chronic myeloid leukaemia, or CML. Treatment of CML usually relies on inhibitors of the abnormal protein that causes the condition but some patients do not respond to treatment and efforts are underway to develop a supplementary approach, targeting the so-called JAK2 kinase. Recent results from the groups of Veronika Sexl at the University of Veterinary Medicine, Vienna (Vetmeduni Vienna) and Giulio Superti-Furga at the Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM) have called this strategy into question. The work is published in the current issue of the prestigious journal Nature Chemical Biology and is of immediate relevance to leukaemia treatment.
The cause of CML has been known since 1960, when two scientists in Philadelphia, Pennsylvania showed that the disease was associated with a particular genetic abnormality, the "Philadelphia chromosome". Philadelphia chromosomes represent the result of an incorrect crossing-over between two chromosomes, through which part of the Bcr ("breakpoint cluster region") gene from chromosome 22 fuses with the Abl gene on chromosome 9. The fusion gene product is a tyrosine kinase, i.e. it can phosphorylate other proteins on tyrosine residues. When it does so, it incorrectly activates several signal pathways controlling cell division in white blood cells and leads to leukaemia. Thankfully, drugs have been developed that prevent the kinase activity of the BCR-ABL fusion protein and the majority of patients treated with such tyrosine kinase inhibitors (e.g. imatinib) show no further signs of leukaemia.
Unfortunately, however, patients may develop resistance to the therapy so an alternative approach is required. Recent developments have focused on the use of drugs targeting another kinase involved in CML, the JAK2 kinase. In normal white blood cells, JAK2 is known to activate a further molecule, known as STAT5, which is absolutely required for the development of CML. The argument runs that if JAK2 could be specifically inhibited and thus STAT5 not activated it would bring fresh hope to patients who do not respond to treatment with imatinib. Several potential inhibitors of JAK2 are currently undergoing clinical trials and may shortly be available for treating patients.
The theory is appealing but to date we do not really understand exactly what happens when JAK2 is inactivated following the initiation of leukaemia by the Bcr-Abl oncogene. Sexl and her colleagues have used a transgenic mouse model to clarify the functions of these proteins in leukaemia. Their results were highly unexpected. The JAK2 kinase was found to be not required for the maintenance of the disease, i.e. inhibiting JAK2 in leukaemic cells had no therapeutic benefit. However, inhibition of STAT5 in leukaemia was sufficient to prevent cell proliferation. As Sexl says, "this means that the normal signalling pathway is completely rewired in CML cells: STAT5 activity no longer depends on JAK2." In support of this conclusion, the researchers were able to show that the BCR-ABL protein directly phosphorylates STAT5, thereby activating it.
As Superti-Furga notes, "The findings have extremely important consequences for CML therapy in humans," adding, "We are very happy that the collaboration between our two groups is so fruitful". Put bluntly, leukaemia patients that do not respond to imatinib will not be helped by inhibiting JAK2. Interestingly, some JAK2 inhibitors do slow the progression of leukaemic cells, although they must be given at very high levels. The "therapeutic" action is mediated by a secondary target of the JAK2 inhibitors, which Sexl and colleagues have shown to be the Bcr-Abl oncogene itself. Sexl concludes that, "at the moment there is simply no rationale for giving leukaemic patients JAK2 inhibitors. If we want to help patients who do not respond to imatinib, we should concentrate instead on developing inhibitors to STAT5."
More information: dx.doi.org/10.1038… NChemBio.775
Journal reference: Nature Chemical Biology
Provided by University of Veterinary Medicine -- Vienna
- Targeting leukemia cell's gene 'addiction' presents new strategy for treatment Mar 03, 2010 | not rated yet | 0
- Activation of LYN kinase is associated with imatinib-resistance in CML patients Jun 25, 2008 | not rated yet | 0
- Scientists discover how to beat resistance to standard leukaemia drug Dec 09, 2011 | not rated yet | 0
- Combination of 2 novel anti-cancer agents may help fight CML resistant to current therapy May 29, 2008 | not rated yet | 0
- Can cancer drugs combine forces? Aug 16, 2007 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Pressure-volume curve: Elastic Recoil Pressure don't make sense
22 hours ago From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
Ratio of Hydrogen of Oxygen in Dessicated Animal Protein
May 13, 2013 As an experiment, for the past few months I've been consuming at least one portion of Jell-O or unflavored Knox gelatin per day. I'm 64, in very...
Alcohol and acetaminophen
May 13, 2013 Edit: sorry for the typo in the title , can't edit I looked around on google quite a bit and it's very hard to find precise information on the...
Marie Curie's leukemia
May 13, 2013 Does anyone know what might be the cause of Marie Curie's cancer
- More from Physics Forums - Medical Sciences
More news stories
The use of a smartphone application significantly improves patients' preparation for a colonoscopy, according to new research presented today at Digestive Disease Week (DDW). The preparation process, which begins days in ...
Cancer 27 minutes ago | not rated yet | 0
Research presented at Digestive Disease Week (DDW) explores new methods for managing digestive health through diet and lifestyle.
Cancer 47 minutes ago | not rated yet | 0
A ground-breaking advance in colonoscopy technology signals the future of colorectal care, according to research presented today at Digestive Disease Week(DDW). Additional research focuses on optimizing the minimal withdrawal ...
Cancer 15 hours ago | 5 / 5 (2) | 0
(HealthDay)—Concurrent use of two immune checkpoint antibodies—ipilimumab and nivolumab—may be effective for the treatment of advanced melanoma, according to a proof-of-principal study presented in ...
Cancer May 17, 2013 | not rated yet | 0
(HealthDay)—The risks of metastasis and death associated with cutaneous squamous cell carcinoma (CSCC) are low, but significant, and risk factors for poor outcome include tumor diameter, invasion beyond ...
Cancer May 17, 2013 | not rated yet | 0 |
Regular consumption of coffee is associated with a reduced risk of primary sclerosing cholangitis (PSC), an autoimmune liver disease, Mayo Clinic research shows. The findings were being presented at the Digestive Disease ...
1 hour ago | not rated yet | 0 |
Patients with treatment-resistant major depression saw dramatic improvement in their illness after treatment with ketamine, an anesthetic, according to the largest ketamine clinical trial to-date led by researchers from the ...
58 minutes ago | 4.5 / 5 (2) | 0 |
There are significant cost and risk factors associated with two procedures commonly used to diagnose or treat gastrointestinal problems, according to research presented at Digestive Disease Week (DDW).
37 minutes ago | not rated yet | 0
An increasing number of U.S. children are experiencing gastrointestinal issues that require interventions to resolve, according to research presented at Digestive Disease Week (DDW).
15 hours ago | not rated yet | 0 |
The latest makeover to a massive psychiatric tome honored by some, reviled by others and even called the "Bible" of mental disorders is being released Saturday with a host of new changes.
13 hours ago | not rated yet | 0