SC notice on marketing rights of drug

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Our Legal Correspondent
NEW DELHI, Aug. 6. – The Supreme Court (coram, Sabharwal, Dharmadhikari, JJ) today issued notices to the Centre, the health ministry, the Controller General of Patents and the Drug Controller General of India on a PIL challenging the government decision to grant exclusive marketing rights of a generic cancer drug to Swiss pharma major, Novartis AG, under TRIPS.

The PIL, filed by the Cancer Patients Aid Association, said that the Centre’s move to grant such exclusive marketing rights to a foreign company which will have a monopoly over the product would result in the prices of the drug, Gleevec, escalating from the current Rs 4,000 per month to Rs 1,20,000 per month for any patient suffering from Chronic Myeloid Leukaemia (CML).

“…This is violative of Articles 14 and 21 of the Constitution,” the petition said. As the procedure laid down by the Patents Act, 1955, does not provide for opposition or revocation of the exclusive marketing rights (EMR) before five years when the patent application for the product can be rejected. Besides, the law also permits the EMR holder to sue for infringement of their patent during these five years.

The petition urged that under Section 24 C of the Patents Act, the government could provide for compulsory licensing of these drugs in “public interest” but the executive has come up with a rule that this can be done only after two years from the date of approval granted for the exclusive right to sell or distribute under Section 24 B.

“Rational consideration requires that the power of compulsory license, which are in any case for the protection of public health, should be exercisable forthwith,” it stated. It alleged that the rule-making authority has misused its power to to restrict public interest to mean national or extreme urgency. Such a narrow interpretation of the term was not intended by the legislature, it said.
The petitioner association also sought the court’s intervention for the fixation of the upper limit on such vital drugs.

Chemical in betel leaf could develop into a treatment for CML

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Chemical in betel leaf ‘could cure type of cancer’
Ranjita Biswas
6 August 2004
Source: SciDev.Net

[KOLKATA] Scientists at the Indian Institute of Chemical Biology (IICB) in Kolkata claim to have discovered a potential cure for a form of leukaemia in the common betel leaf. Locally known as paan, the leaf is widely chewed as an aid to digestion.

“Our research is a breakthrough in the sense that this is the first time a molecule from a plant has specifically destroyed cancerous cells without producing any harmful effect on normal cells,” says Samir Bhattacharya, IICB director.

The researchers discovered the substance in the leaves of the betel plant (Piper betel) while studying the medical potential of various herbal remedies used in India.

The compound, known as chlorogenic acid, kills cancerous cells in chronic myeloid leukaemia (CML) but leaves non-cancerous cells unharmed, according to researcher Santu Banerjee. This form of cancer attacks white blood cells.

Following the discovery, experiments were conducted using the compound on cancer cells obtained from Europe, Japan and the United States. Next, in collaboration with medical institutes, blood cells from patients with chronic leukaemia were treated with it. In all the studies, the cancerous cells were totally destroyed. Studies using live mice with CML also demonstrated a complete success.

The IICB is in talks with the Indian Council for Medical Research about clinical trials on humans. “Hopefully, these will be possible in the near future,” says Bhattacharya.

Concerns have been raised in the past about potential health risks associated with paan-chewing, specifically oral cancer. But Bhattacharya says that the link has not been proved conclusively by any study, though there are some studies showing adverse effects of the betel nut, which is usually chewed together with the paan leaves. But those studies have not been based on animal experiments, according to Bhattacharya.

If proven effective, this discovery could lead to an affordable treatment for leukaemia patients, especially in poorer countries, as betel plants grow abundantly in South Asia. Currently, the drug of choice for treating CML is Gleevec, manufactured by the multinational Novartis.

The research, which ran for more than three years, has been accepted for publication in Blood, the international journal of the Haematological Society of America.


Cancer drug mktg rights to Novartis AG: SC issues notice to Centre

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Cancer drug mktg rights to Novartis AG: SC issues notice to Centre

NEW DELHI: The Supreme Court today issued notices to Centre, Controller General of Patents and the Drug Controller General of India on a petition challenging grant of exclusive marketing rights (EMR) of cancer drug to a Swiss MNC Novartis AG.

The petition filed by Cancer Patients Aid Association alleged that this has created a monopoly of cancer drugs in favour of the Swiss company and alleged that the drug which is now available to patients at a discounted price of Rs 4,000 would cost Rs 1,20,000. – PTI

SC notice on Novartis EMR

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SC notice on Novartis EMR
Press Trust of India / Chennai August 06,2004
The Supreme Court (SC) today issued notices to the central government, Controller General of Patents and the Drug Controller General of India on a petition challenging grant of exclusive marketing rights (EMR) of a cancer drug to Novartis AG.

The petition, filed by Cancer Patients Aid Association, alleged that this has created a monopoly of cancer drugs in favour of the company,  and alleged that the drug, which is now available to patients at a discounted price of Rs 4,000, would cost Rs 1,20,000.

Supreme Court In India Issues Notice On Novartis Suit

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India News > Court notice on cancer drugs marketing rights:

New Delhi, Aug 6 (IANS) :

The Supreme Court Friday issued notices to the central government and others on a petition alleging that price of a drug for treatment of cancer would spiral if its exclusive marketing rights were awarded to a particular company.

A bench comprising judges Y.K. Sabharwal and D.M. Dharmadhikari issued notices to the centre, the Drug Controller of India, Controller General of Patents and National Pharmaceutical Pricing Authority on the petition against granting exclusive marketing rights to the Swiss pharmaceuticals major Novartis AG.

The court also issued notice to Novartis AG and its Indian firm Novartis India Limited on the petition filed by the Cancer Patients Aid Association (CPAA).

CPAA challenged the grant of marketing rights to Novartis of the drug Gleevec, containing crystalline form of a compound Imatinib Meyslate, used in treating patients suffering from Chronic Myeloid Leukemia — a life-threatening form of cancer.

As a result of this, Gleevec prices would go up from the present Rs.4,000 to Rs.120,000, the petitioner alleged.

It said an overwhelming majority of 24,000 patients who suffered from Chronic Myeloid Leukemia every year in India would die, as the drug would become unaffordable for most people.

The petitioner said since it was an essential life-saving drug, the centre should exercise its powers in public interest and fix its price so that patients can afford it.

Kids’ Trike-A-Thon helps fight cancer

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Kids’ Trike-A-Thon helps fight cancer

Samantha Graham, 5, goes around the inner track while another rider passes on the outside during a Trike-A-Thon held Thursday at Little Angels Childcare Center. The daycare raised money for St. Jude’s Children’s Research Hospital. – Mike Buckley/Fremont Tribune

By Beverly J. Lydick/Tribune staff

Astride a tiny two-wheeler with a black plastic pot for a basket, he pedals slowly through a maze of orange construction cones set up on the Bell Field Elementary School playground.

OK, so he’s not exactly Lance Armstrong.

But Hunter Maslonka, 8, still shares common ground with the six-time winner of the Tour De France.

Both are cancer survivors and both ride bikes to raise money for cancer research.

While Armstrong works through the Austin, Texas, foundation that bears his name, Hunter relies on the staff and students at Little Angels Day Care.

Wednesday marked the facility’s second annual Trike-A-Thon, where Little Angel clients rode laps around a course while staff members kept track of their efforts. Pay-per-lap donors solicited before Wednesday’s event will find out how much they owe when the bikers return with their tally sheets.

Each child sets his or her own goal, with the whole group working to beat last year’s effort. In 2003, the young cyclists raised $270, which was donated to St. Jude’s Children’s Research Hospital in Memphis, Tenn.

Hunter is doing his part to send even more this year. Prior to Wednesday’s ride, he was knocking on doors and explaining his plan.

“I say I’m raising money for sick

people,” he says. “I say I had cancer.”

Hunter’s mother, Amy Maslonka, says her son was diagnosed with juvenile chronic myelogenous leukemia when he was just 6 weeks old. At 7 months, he received a bone marrow transplant from his brother, Dakota, who was 3 at the time.

Following the transplant, Hunter suffered a relapse which put him on life support for a month. But he rallied, received another marrow transplant at 15 months, and has been in remission ever since.

The cancer – and what it took to beat it – took a toll on Hunter.

At 8, he weighs 40 pounds. His teeth are damaged by the chemotherapy and he has difficulty speaking clearly. His mother says he will always be small for his age.

But when it comes to confidence, Hunter is big. Someday, he wants to be president.

But right now, his personal Trike-A-Thon goal is $100. He says he’s already raised $16.

Amy says it’s more like $60. She’s watched as he’s made his door-to-door plea.

“He says he’s raising money for cancer research and people just look at him, because he’s so small,” she says.

One woman seemed to doubt Hunter’s doorstep testimonial.

“She said, ‘You had cancer?’” recalls Amy. “And Hunter said, ‘Yeah, I did.’”

Little Angels’ clients have until Thursday to collect their pledges. Amy has no doubt her son will meet his goal.

“Trust me,” she says, “he’ll make it.”

Copyright © 2004  Fremont Tribune

Donor APCs are required for maximal GVHD but not for GVL.

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Nat Med. 2004 Aug 1;
Matte CC, Liu J, Cormier J, Anderson BE, Athanasiadis I, Jain D, McNiff J, Shlomchik WD

Graft-versus-host disease (GVHD) is a major source of morbidity in allogenic stem cell transplantation. We previously showed that recipient antigen-presenting cells (APCs) are required for CD8-dependent GVHD in a mouse model across only minor histocompatibility antigens (minor H antigens). However, these studies did not address the function of donor-derived APCs after GVHD is initiated. Here we show that GVHD develops in recipients of donor major histocompatibility complex class I-deficient (MHC I(-)) bone marrow. Thus, after initial priming, CD8 cells caused GVHD without a further requirement for hematopoietic APCs, indicating that host APCs are necessary and sufficient for GHVD. Nonetheless, GVHD was less severe in recipients of MHC I(-) bone marrow. Therefore, once initiated, GVHD is intensified by donor-derived cells, most probably donor APCs cross-priming alloreactive CD8 cells. Nevertheless, donor APCs were not required for CD8-mediated graft-versus-leukemia (GVL) against a mouse model of chronic-phase chronic myelogenous leukemia. These studies identify donor APCs as a new target for treating GVHD, which may preserve GVL.

Two different point mutations in ABL gene ATP-binding domain conferring Primary Imatinib resistance in a Chronic Myeloid Leukemi

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Biol Proced Online. 2004; 6: 144-148
Iqbal Z, Siddiqui RT, Qureshi JA

Imatinib (Gleevec) is the effective therapy for BCR-ABL positive CML patients. Point mutations have been detected in ATP-binding domain of ABL gene which disturbs the binding of Gleevec to this target leading to resistance. Detection of mutations is helpful in clinical management of imatinib resistance. We established a very sensitive (ASO) PCR to detect mutations in an imatinib-resistant CML patient. Mutations C944T and T1052C were detected which cause complete partial imatinib resistance, respectively. This is the first report of multiple point mutations conferring primary imatinib resistance in same patient at the same time. Understanding the biological reasons of primary imatinib resistance is one of the emerging issues of pharmacogenomics and will be helpful in understanding primary resistance of molecularly-targeted cancer therapies. It will also be of great utilization in clinical management of imatinib resistance. Moreover, this ASO-PCR assay is very effective in detecting mutations related to imatinib resistance.

Use of denaturing HPLC for detection of mutations in the BCR-ABL kinase domain in patients resistant to Imatinib

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Use of denaturing HPLC for detection of mutations in the BCR-ABL kinase domain in patients resistant to Imatinib.

Clin Chem. 2004 Jul; 50(7): 1233-7
Irving JA, O’Brien S, Lennard AL, Minto L, Lin F, Hall AG

Erythropoietin Overcomes Imatinib-Induced Apoptosis and Induces Erythroid Differentiation in TF-1/bcr-abl Cells.

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Stem Cells. 2004; 22(4): 609-16
Uchida M, Watanabe T, Kunitama M, Mori M, Kikuchi S, Yoshida K, Kirito K, Nagai T, Ozawa K, Komatsu N

Targeting BCR-ABL tyrosine kinase by treatment with the selective inhibitor imatinib (formerly STI571, Gleevec) has proved to be highly efficient for inhibiting leukemic growth in vitro. In addition, in clinical trials, imatinib has produced high response rates in patients with chronic myeloid leukemia (CML) in chronic phase and blastic crisis. However, episodes of severe cytopenia were also frequently observed, leading to discontinuation of therapy in some cases. Therefore, it is important to examine whether administration of cytokines overcomes the adverse effects of imatinib in in vitro systems. In this study, we examine the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO) on TF-1/bcr-abl (which was generated by transduction of a bcr-abl fusion gene into the TF-1 cell line) as a model system for CML with blastic crisis. Imatinib induced apoptosis in TF-1/bcr-abl cells but not in the parental TF-1 cells. However, GM-CSF, a survival factor of the parental TF-1 cells, protected TF-1/bcr-abl cells from imatinib-induced apoptosis in a dose-dependent manner. Concomitantly, constitutive phosphorylation of Stat5 and FKHRL1 was significantly inhibited by imatinib, and the inhibition was canceled by the addition of GM-CSF, accompanied by upregulation of Bcl-xL and downregulation of p27/Kip1. In addition, although untreated TF-1/bcr-abl cells had lost responsiveness to both GM-CSF and EPO and showed autonomous growth, GM-CSF enhanced phosphorylation of Stat5 and FKHRL1 in these cells. Importantly, imatinib-treated TF-1/bcr-abl cells differentiated into hemoglobin-positive cells in the presence of EPO, as in the case for the parental TF-1 cells. Taken together, imatinib-treated CML cells may differentiate into mature cells in the presence of differentiation-inducing cytokines such as EPO.

Caenorhabditis elegans ABL-1 antagonizes p53-mediated germline apoptosis after ionizing irradiation.

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Nat Genet. 2004 Aug; 36(8): 906-12
Deng X, Hofmann ER, Villanueva A, Hobert O, Capodieci P, Veach DR, Yin X, Campodonico L, Glekas A, Cordon-Cardo C, Clarkson B, Bornmann WG, Fuks Z, Hengartner MO, Kolesnick R

c-Abl, a conserved nonreceptor tyrosine kinase, integrates genotoxic stress responses, acting as a transducer of both pro- and antiapoptotic effector pathways. Nuclear c-Abl seems to interact with the p53 homolog p73 to elicit apoptosis. Although several observations suggest that cytoplasmic localization of c-Abl is required for antiapoptotic function, the signals that mediate its antiapoptotic effect are largely unknown. Here we show that worms carrying an abl-1 deletion allele, abl-1(ok171), are specifically hypersensitive to radiation-induced apoptosis in the Caenorhabditis elegans germ line. Our findings delineate an apoptotic pathway antagonized by ABL-1, which requires sequentially the cell cycle checkpoint genes clk-2, hus-1 and mrt-2; the C. elegans p53 homolog, cep-1; and the genes encoding the components of the conserved apoptotic machinery, ced-3, ced-9 and egl-1. ABL-1 does not antagonize germline apoptosis induced by the DNA-alkylating agent ethylnitrosourea. Furthermore, worms treated with the c-Abl inhibitor STI-571 (Gleevec; used in human cancer therapy), two newly synthesized STI-571 variants or PD166326 had a phenotype similar to that generated by abl-1(ok171). These studies indicate that ABL-1 distinguishes proapoptotic signals triggered by two different DNA-damaging agents and suggest that C. elegans might provide tissue models for development of anticancer drugs.

Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects.

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J Clin Invest. 2004 Aug; 114(3): 379-88
Borg C, Terme M, Ta�¯eb J, M�©nard C C, Flament C, Robert C, Maruyama K, Wakasugi H, Angevin E, Thielemans K, Cesne AL, Chung-Scott V V, Lazar V, Tchou I, Cr�©pineau F, Lemoine F, Bernard J, Fletcher JA, Turhan A, Blay JY, Spatz A, Emile JF, Heinrich MC, M�©cheri S, Tursz T, Zitvogel L

Mutant isoforms of the KIT or PDGF receptors expressed by gastrointestinal stromal tumors (GISTs) are considered the therapeutic targets for STI571 (imatinib mesylate; Gleevec), a specific inhibitor of these tyrosine kinase receptors. Case reports of clinical efficacy of Gleevec in GISTs lacking the typical receptor mutations prompted a search for an alternate mode of action. Here we show that Gleevec can act on host DCs to promote NK cell activation. DC-mediated NK cell activation was triggered in vitro and in vivo by treatment of DCs with Gleevec as well as by a loss-of-function mutation of KIT. Therefore, tumors that are refractory to the antiproliferative effects of Gleevec in vitro responded to Gleevec in vivo in an NK cell-dependent manner. Longitudinal studies of Gleevec-treated GIST patients revealed a therapy-induced increase in IFN-gamma production by NK cells, correlating with an enhanced antitumor response. These data point to a novel mode of antitumor action for Gleevec.

The hematopoietic stem cell in myelodysplasia.

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Stem Cells. 2004; 22(4): 590-9
Liesveld JL, Jordan CT, Phillips GL

The mechanisms underlying hematopoietic stem cell or progenitor cell abnormalities in myelodysplastic syndromes (MDSs) remain poorly characterized. Current evidence exists for multiple intrinsic and extrinsic influences upon the stem cell in these disorders. These influences are outlined in this review and include: stem cell characteristics in MDSs, as compared with those in acute myelogenous leukemia; the role of increased apoptosis; the role of signaling pathway abnormalities; the influences of immune modulation; and the effect of stromal cells and stromal cell cytokine production. Despite numerous studies that have examined these factors, how they converge to produce a situation in which accelerated proliferation and accelerated death occur simultaneously remains largely an unexplored area. It is anticipated that future studies that focus on well-characterized and purified progenitor populations in these disorders will elucidate the process by which ineffective hematopoiesis results from the influences of stem cell abnormalities versus abnormalities in the stem cell’s microenvironmental and immunologic milieu.

Plasma basic fibroblast growth factor and bone marrow fibrosis in clonal myeloproliferative disorders.

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Clin Lab Haematol. 2004 Aug; 26(4): 265-8
Sayinalp N, Cinar H, Uner A, Haznedaro�Ÿlu IC, B�¼y�¼ka�Ÿik Y, G�¶ker H, Aksu S, Ozcebe OI, Karaku�Ÿ S, Kirazli S, D�¼ndar SV

Summary Basic fibroblast growth factor (bFGF) is an important growth factor involved in clonal hematopoietic expansion, neoangiogenesis, and bone marrow fibrosis, all of which are important pathobiologic features of clonal chronic myeloproliferative disorders (CMPD) and myelodysplastic syndromes (MDS). The aim of this study was to assess circulating bFGF concentrations in patients with CMPD and MDS with respect to the presence of bone marrow fibrosis in histopathologic examination. The study group comprised 18 patients with CMPD (six female, 12 male; median age 50 years), seven patients with MDS (one female, six male; median age 66 years) and 10 healthy adults as controls (four female, six male; median age 29 years). CMPD group included six chronic myelogenous leukemia (CML), seven essential thrombocythemia (ET), three polycythemia vera (PV), two agnogenic myeloid metaplasia (AMM). All seven MDS patients were the FAB subtype of refractory anemia (RA). Bone marrow biopsy sections stained with hematoxylin and eosin (H & E) and for reticulin were examined for the presence of fibrosis. The median plasma bFGF level was 18.2 pg/ml (interquartile range, IQR: 15.2-26.7) in patients with CMPD, 18.0 pg/ml (IQR: 15.8-26.4) in patients with MDS, 13.6 pg/ml (IQR: 9.9-20.0) in the control group. The bFGF levels were significantly higher in patients with CMPD in comparison with the healthy control group (P = 0.031). Circulating bFGF tended to be significantly lower in relation to the development of marrow fibrosis (P = 0.028). The complicated interactions of bFGF and fibrosis in the context of CMPD may be either ’cause’ or ‘effect’. The bFGF might represent an important link between angiogenesis, fibrosis, and clonal neoplastic hematopoiesis during the development of CMPD.

[The mechanisms of the resistance to molecular targeting agents]

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[The mechanisms of the resistance to molecular targeting agents]
Nippon Rinsho. 2004 Jul ; 62(7): 1297-304
Increasing knowledge of the mechanism of the initiation and progression of various cancers is the catalyst for developing new anticancer therapeutics that target specific molecules expressed in cancer cells. STI571 (imatinib mesylate) is an example of the successful development of a rationally designed and targeted agent. Its target is the constitutively active tyrosine kinase, BCR-ABL in chronic myelogenous leukemia (CML). Clinical studies with STI571 in CML demonstrated that many patients with advanced stage disease respond initially but then relapse. Drug resistance is associated with the reactivation of BCR-ABL signal transduction. Another targeted protein-tyrosine kinase inhibitor that was approved for clinical use is ZD1839 (Iressa). ZD1839 is an orally active and selective inhibitor for epidermal growth factor receptor (EGFR) tyrosine kinase. HER2 is overexpressed in 25-30% of breast cancers and associated with shorter time to relapse and lower survival rate. Specific targeting of these cancers can be accomplished with Herceptin directed against the extracellular domain of the HER2 protein. However, even in the selected group of patients with high levels of HER2, the response to Herceptin is limited in magnitude and duration. The mechanisms of the resistance to these targeted agents were reviewed.

[Imatinib therapy for patients with chronic myelogenous leukemia]

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[Imatinib therapy for patients with chronic myelogenous leukemia]
Nippon Rinsho. 2004 Jul ; 62(7): 1325-31
Imatinib mesylate (imatinib), a selective inhibitor of BCR-ABL tyrosine kinase, has shown excellent efficacy in patients with chronic myelogenous leukemia (CML) in the chronic phase, however, it does not in those in the accelerated phase or blastic crisis. In patients with CML who have undergone allogeneic stem cell transplantation, imatinib has the capability to induce hematological and even molecular response, and provides a prolonged survival among those in the chronic and accelerated phases. It has been demonstrated that major cytogenic response is a surrogate marker for survival in cases receiving imatinib. It has also been demonstrated that a genome-wide cDNA microarray enables the prediction of sensitivity to imatinib. The acquired resistance in patients who failed to respond to imatinib seemed to be induced by several point mutations in the BCR-ABL gene, which were likely to affect the binding of imatinib with BCR-ABL. Polyclonal cells which harbor distinct mutations in a single patient seemed to be selected in vivo under the selective pressure of imatinib, indicating the rationale of combined treatment with other types of agents. Recently, SPIRIT (STI571 Prospective International Randomized Trials) have been conducted, in which the efficacy of imatinib monotherapy, and imatinib combined with interferon or cytarabine were compared. New agents which inhibit the signaling pathway related to BCR-ABL, such as adaphostin (NSC680410), farnesyltransferase inhibitor SCH66336, MAP kinase inhibitor PD184352, PD98059, U0126, and antibiotic geldanamycin, have shown excellent activity combined with imatinib in vitro.

Cytoplasmic mislocalization of p27Kip1 protein

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Cytoplasmic mislocalization of p27Kip1 protein is associated with constitutive phosphorylation of Akt or protein kinase B and poor prognosis in acute myelogenous leukemia.

Cancer Res. 2004 Aug 1; 64(15): 5225-31
Cyclin-dependent kinase inhibitor p27Kip1 functions at the nuclear level by binding to cyclin E/cyclin-dependent kinase-2. It was shown that Akt or protein kinase B (Akt/PKB)-dependent phosphorylation of p27Kip1 led to the cytoplasmic mislocalization of p27Kip1, suggesting the potential abrogation of its activity. Here, we evaluated the localization of p27Kip1 protein in leukemic blasts in relation to Akt/PKB phosphorylation and clinical outcomes in acute myelogenous leukemia (AML). Western blot analysis of the nuclear and cytoplasmic fractions revealed a heterogenous localization pattern of p27Kip1 in AML. Cytoplasmic mislocalization of p27Kip1 was significantly associated with the constitutive serine(473) Akt/PKB phosphorylation in AML cells (P < 0.05). Transfection of U937 cells with an expression construct encoding the constitutively active form of Akt/PKB resulted in a remarkable increase in the levels of cytoplasmic p27Kip1. Whereas the transfection of U937 cells with a construct encoding dominant-negative Akt/PKB resulted in a recovery of nuclear localization of p27Kip1. Both the disease-free survival and overall survival are significantly shorter in AML cases with high cytoplasmic to nuclear ratio of p27Kip1 localization compared with the cases with low cytoplasmic to nuclear ratio (P = 0.0353, P = 0.0023, respectively). Multivariate analysis indicated that the cytoplasmic to nuclear ratio of p27Kip1 localization was an independent prognostic variable for both disease-free survival and overall survival (P = 0.043, P = 0.008, respectively). These findings additionally extend our understanding of the role of p27Kip1 in AML, and buttress the case of p27Kip1 mislocalization as a prognostic indicator and Akt/PKB/p27Kip1 pathway as a ready target for antileukemia therapy.

Effect of mutational inactivation of tyrosine kinase activity on BCR/ABL-induced abnormalities

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Effect of mutational inactivation of tyrosine kinase activity on BCR/ABL-induced abnormalities in cell growth and adhesion in human hematopoietic progenitors.
Cancer Res. 2004 Aug 1; 64(15): 5322-31
Chronic myelogenous leukemia (CML) results from transformation of a primitive hematopoietic cell by the BCR/ABL gene. The specific BCR/ABL signaling mechanisms responsible for transformation of primitive human hematopoietic cells are not well defined. Previous studies have suggested that constitutively activated tyrosine kinase activity plays an important role for in abnormal proliferation of CML progenitors but has not clearly defined its role in abnormal adhesion and migration. We established a human progenitor model of CML by ectopic expression of BCR/ABL in normal CD34+ cells using retrovirus-mediated gene transfer. CD34+ cells expressing BCR/ABL demonstrated several features characteristic of primary CML progenitors including increased proliferation in committed and primitive progenitor culture, reduced adhesion to fibronectin, and reduced chemotaxis to stroma-derived factor-1alpha. We expressed a kinase-inactive BCR/ABL gene to directly investigate the role of kinase activity in abnormal progenitor function. Abnormalities in proliferation were completely reversed, whereas defects in adhesion and migration were significantly improved but not completely reversed in cells expressing a kinase-inactive BCR/ABL. Furthermore, the BCR/ABL kinase inhibitor imatinib mesylate markedly inhibited proliferation of BCR/ABL-expressing progenitors but did not fully correct the adhesion and migration defects. Expression of BCR/ABL genes with deletions of either the COOH-terminal actin binding or proline-rich domains resulted in enhanced adhesion and chemotaxis compared with wild-type BCR/ABL but did not affect progenitor proliferation. We conclude that abnormal kinase activity is essential for abnormal proliferation and survival of CML progenitors but that abnormal adhesion and migration result from both kinase-dependent and -independent mechanisms.

Pic Of The Day

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A couple hold hands in front of a fountain on Athens’ main Syntagma Square which reopened after months of renovation work.