Hi there ...

Hi Lou,

I did a little research and it seems that JAK2 is one of the Janus tyrosine kinase family and is implicated in the development of myeloproliferative disorders ... which are:
chronic myelogenous leukaemia (CML), polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IM)

I have copied an article below about this by Prof.Francois-Xavier Mahon which explains this further although it might be a little technical, but with careful reading it seems that JAK2 could be present in some cases of CML... -which is an MPD- and means that the JAK2 kinase is found to be abnormally activated.

I would suggest asking your doctor if being JAK2 positive is 'par for the course' in all cases of CML or if it is only found in some cases. If the latter is true then the next question would be ... how does this affect my response to therapy?
I hope this helps,
best wishes,

Sandy

Oncogene (2005) 24, 7125–7126.
doi:10.1038/sj.onc.1208885;
published online 4 July 2005

JAK the trigger

François-Xavier Mahon

1Laboratoire d'hématopoïèse leucémique et cible thérapeutique, Université Victor Segalen Bordeaux 2, Service des maladies du sang CHU de Bordeaux, INSERM E0217, 146 rue Léo Saignat, Boite 50, 33076 Bordeaux Cedex, France

Correspondence: F-X Mahon, E-mail: francois-xavier.mahon@umr5540.u-bordeaux2.fr

Abstract

A somatic mutation that leads to activation of the JAK2 tyrosine kinase has recently been identified as a recurrent genetic abnormality in several different myeloproliferative disorders. A translocation generating the constitutively activated fusion protein PCM1-JAK2 has also been recently found in atypical chronic myelogenous leukemia and acute leukemia. This recent spate of independent studies (one of which is published in this issue of Oncogene) establish abnormal JAK2 activation as the underlying defect in a significant number of cases of myeloproliferative disease, and JAK2 as an important new therapeutic target.

Keywords:
tyrosine kinases, leukemia, JAK2

A number of diseases including cancer are linked to dysregulation of tyrosine kinases. More than 500 proteins with kinase activity are coded by the human genome, but only 90 or so are tyrosine kinases. Exchange of phosphate between different substrates is the intracellular mode to communicate. This molecular language is precisely regulated by protein kinases or phosphatases. However, these enzymes may be dysregulated and activated in cancer cells leading to a loss of normal cell growth control.

The hematopoietic cytokine receptors receive growth signals from outside the cell and transduce these via their cytoplasmic tails by activating members of the Janus kinase (JAK) family of tyrosine kinase proteins, which phosphorylate cytoplasmic targets. JAK2 is one member of this family and is critical to the signalling of many hematopoietic cytokine and growth factor receptors (Ihle, 1995). A number of recent studies now implicate the dysregulation of this kinase in the development of myeloproliferative disease.

The myeloproliferative disorders include chronic myelogenous leukaemia (CML), polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IM). For each of these disorders, a particular lineage of myeloid cell is involved and present in excessive numbers in the peripheral blood, that is, granulocytic for CML, erythroid for PV or platelet for ET, while marrow fibrosis predominates in the IM. To these myeloproliferative disorders may also be added hypereosinophilic syndrome (HES), systemic mast cell disease (SMCI), chronic myelomococytic leukemia and atypical CML (aCML). Among all of these diseases, CML is a model because a marker, the Philadelphia chromosome, makes it possible to recognize the abnormal cells and thus to identify its molecular counterpart the BCR-ABL gene. BCR-ABL protein exhibits a constitutive tyrosine kinase activity, which drives leukemic proliferation and preferentially myeloid cell expansion. Outstanding work regarding the understanding of BCR-ABL and its dysregulated kinase has led to focusing research on the protein kinases and their essential role in leukemogenesis. This effort has been underpinned by the discovery of imatinib, which inhibits the kinase activity of BCR-ABL. This is the first tyrosine kinase inhibitor developed for clinical application, and has proved highly successful in CML (Druker et al., 2001).

Hi Lou,
I did some further research about his unusual presentation and it seems that JAK2 is usually found in those diagnosed with MF;PV;ET etc.... ie. myeloproliferative disorders....but not with CML....although it is seen in PH neg or atypical CML (aCML) and CMML etc....

However there have recently been some reports of chronic stage ph+CML with the JAK2 kinase and it is thought that because Glivec does very well to inhibit BCR/ABL, JAK2 -if it is there- then becomes visible.
The thinking is that it was there all along with a previously undiagnosed MPD such as MF-(myelofibrosis)

I read one abstract where the patient was treated with Glivec AND hydroxyurea. I could not access the full text of this paper as I do not have a subscription to The Lancet which is where I found the article.

It is very rare I think so it is not surprising that Kings have not seen this dual presentation before.

However, when I was first diagnosed it was thought that I had primary MF rather than CML. When I got the diagnosis of CML it was thought that the MF was secondary to that... i.e was caused by CML rather than the other way around. But I think at first they thought I had both conditions.
I understand therefore what you are feeling right now!

However, I am still here because I responded well to Glivec for over 3.5 years even with all the complications. Of course as I had secondary MF it disappeared along with CML, at least until a Glivec resistant mutation was found and I lost my CCR

The answer for me was a stem cell transplant (mini) as I already had an identified sibling donor.

I will ask other advocates that I am in touch with if they have access to information on this rare presentation. If I find any more information I will let you know.

Meanwhile, I hope your next consultation at Kings gives you some answers about how to deal with this extra problem.

Why not sign up to attend the Patient Seminar? This way you could access some other expert opinions. Click on the link on the left of this page for details and registration.
Keep in touch,

Sandy

Hello Louise

Sorry to hear about your complications and worries. I am sure that Prof Mufti and co will sort things out for you, they are a very dedicated team. There is a CML support group at Kings, ask Janet Hayden, support nurse, for information about the meetings. My next appointment is 9.30 on Wednesday next week - the 1st Oct, if you would like to meet up for a chat. Just ask at the desk for Pennie - they all know who I am!

I was diagnosed with CML in 2001, and Kings have looked after me for years, there is a very friendly group of patients with CML you can link up with if you want to.

ATB
Pennie

hi Lou,
don't worry about CML or MPD being hereditary... the sort of damage to the stem cell that most researchers think is the cause of these diseases is an aquired damage.... but nobody is certain how this happens other than exposure to radiation.
There may also be other triggers. You will not pass this on to your children through your genes.

Please do join a group if you can.... I know that the one at Kings which Pennie is part of is good.
Please do consider registering for the CML Seminar. You will meet a lot of people that post here, plus lots that don't.... and you will have the chance to ask questions of some of the best haematologists in the UK.... but I am sure, as Pennie has said, that Prof. Mufti will have some answers for you ;o)

Best wishes,
Sandy