Targeting kinases in CML CLL.

نویسنده

  • Varsha Gandhi
چکیده

Among the hematologic malignancies, the genetic lesion in chronic myelogenous leukemia (CML) resulting in Bcr-Abl tyrosine kinase has become a hallmark target for therapeutic intervention. Inhibition of Bcr-Abl tyrosine kinase is a poster child for kinasetargeted therapeutics. Unlike CML, chronic lymphocytic leukemia (CLL) does not have a genetic lesion associated with pathophysiology or biology of the disease. However, in recent years, a few kinases have been identified that compared with normal lymphocytes are overexpressed, constitutively active, or activated by microenvironment factors in pathogenic CLL cells. Corollary to this, selective smallmolecule inhibitors of these kinases provide a new pharmacopeia for CLL (see figure) where for decades nucleoside analogs, alkylating agents, and immunotherapeutics have remained the mainstay in treating this disease. Mature B lymphocytes are essential antibody-producing cells of the immune system with B-cell receptors (BCRs) that recognize foreign antigens. Signals emanating from the BCRs are responsible for development/ maturation, proliferation, maintenance, and activation of normal B lymphocytes.2 Several kinases cooperate with BCR and amplify its signaling cascades. These signaling events are not only prevalent but are overexpressed in malignant B lymphocytes like B-cell CLL.3 In addition, microenvironment interactions further augment similar and same survival pathways in CLL cells. These molecular and cellular biology revelations have identified several kinases that play a strategic and important role in CLL pathophysiology. After understanding the impact of these enzymes, inhibitors have been designed, developed, and tested and have opened up a new horizon in CLL therapy.4 A key mediator of proximal BCR signaling is spleen tyrosine kinase (SYK), which is activated through sequential phosphorylation. The downstream pathway is quite involved and eventually leads to activation of Erk and transcription factors.5 In CLL, this protein kinase is overexpressed and downstream signaling of this enzyme contributes to CLL cell survival.6 A selective inhibitor of this kinase, R406, showed activity in primary CLL lymphocytes that were cocultured with bone marrow stroma cells.7 One of the downstream kinases that is activated by SYK is Bruton tyrosine kinase (BTK), which is an intermediary enzyme in the BCR signaling pathway. It is a cytoplasmic enzyme that is essential in B lymphocyte development, survival, and signaling.8 PCI32765 is a small-molecule BTK inhibitor that forms a specific and irreversible bond with cysteine 481 of the enzyme. In addition to BCR signaling, several lines of evidence suggest a role for B lymphocyte stimulator (BLyS), a tumor necrosis factor superfamily ligand, in B-cell survival and resistance. BLyS stimulation activates 2 independent signaling pathways, Akt/mTOR and Pim2.9 The downstream and target molecule of the BLyS-dependent signaling is the antiapoptotic protein Mcl-1, which has been a hallmark factor for CLL cell survival.10 Pim kinase overexpression was demonstrated in CLL cells and a selective Pim kinase inhibitor, SGI1776, showed cytotoxicity in pathogenic CLL cells without an effect on normal B lymphocytes.11 In the current article, the authors show the importance of yet another kinase, PI3K, in CLL cell survival. The isoform delta of the Unlike CML, CLL cells do not have any selective genetic lesion that is associated with the pathophysiology of the disease. On the contrary, B-cell receptor–mediated signaling and interactions with the microenvironment have been shown to maintain CLL lymphocytes. Unlike a single kinase, Bcr-Abl in CML, CLL offers several kinases to target, and selective small-molecule kinase inhibitors are recognized and tested. PI3K indicates phosphatidylinositol 3-kinase; SYK, spleen tyrosine kinase; and BTK, Bruton tyrosine kinase. Professional illustration by Marie Dauenheimer.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

تشخیص و طبقه بندی انواع لوسمی با استفاده از معیارهای مورفولوژیک سیتوشیمیائی و ایمونولوژیک در بیمارستانهای تهران

221 samples of leukemic patients were studied, using morphologic, cytochemical staining pattern and immunophenotyping criteria. Patients included 63 children and 158 adults. Out of the adult group, 110 cases had acute leukemia including 67% AML, 330'{' ALL. In this group, 24 cases of CML" 19 cases of CLL, 4 cases of HCL and one case of plasma cell leukemia were classified. Out of 63 cases of le...

متن کامل

Appearance and Disappearance of Chronic Myeloid Leukemia (CML) in Patient with Chronic Lymphocytic Leukemia (CLL)

Chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML) are the most common leukemias of the elderly (>43 year). However, the sequential occurrence of CML followed by CLL in the same patient is extremely rare. In our report, a 52-year-old female was diagnosed with CLL (type of bone marrow (BM) infiltration was nodular and interstitial) and was treated with chlorambucil. 64 months ...

متن کامل

Nurture versus nature: the microenvironment in chronic lymphocytic leukemia.

Intrinsic factors such as genetic lesions, anti-apoptotic proteins, and aberrant signaling networks within leukemia cells have long been the main focus of chronic lymphocytic leukemia (CLL) research. However, over the past decade, it became increasingly clear that external signals from the leukemia microenvironment make pivotal contributions to disease progression in CLL and other B-cell malign...

متن کامل

Expression of Multidrug Resistance 1, Lung Resistance Protein and Breast Cancer Resistance Protein Genes in Chronic Leukemias

One of the major problems in treatment of leukemias is multidrug resistance, which is already present at diagnosis or develops after chemotherapy. The gene expression levels of multidrug resistance resistance 1 (MDR1), breast cancer resistance protein (BCRP) and lung resistance-resistance protein (LRP) were evaluated in blood samples of 20 CLL and 24 CML patients using RT-PCR. MDR1, BCRP and LR...

متن کامل

B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406.

Antigenic stimulation through the B-cell antigen receptor (BCR) is considered to promote the expansion of chronic lymphocytic leukemia (CLL) B cells. The spleen tyrosine kinase (Syk), a key component of BCR signaling, can be blocked by R406, a small-molecule Syk inhibitor, that displayed activity in CLL patients in a first clinical trial. In this study, we investigated the effects of BCR stimul...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • Blood

دوره 116 12  شماره 

صفحات  -

تاریخ انتشار 2010