Posted by rob on September 28, 2009 under Uncategorized | 
The level of BCR-ABL1 kinase activity before treatment does not identify chronic myeloid leukemia patients who fail to achieve a complete cytogenetic response on imatinib.
Haematologica. 2009 Jun;94(6):861-4
Authors: Khorashad JS, Wagner S, Greener L, Marin D, Reid A, Milojkovic D, Patel H, Willimott S, Rezvani K, Gerrard G, Loaiza S, Davis J, Goldman J, Melo J, Apperley J, Foroni L
Imatinib is currently the first line therapy for newly diagnosed patients with chronic myeloid leukemia. However, 20-25% of patients do not achieve durable complete cytogenetic responses. The mechanism underlying this primary resistance is unknown, but variations in BCR-ABL1 kinase activity may play a role and can be investigated by measuring the autophosphorylation levels of BCR-ABL1 or of a surrogate target such as Crkl. In this study we used flow cytometry to investigate the in vitro inhibition of Crkl phosphorylation by imatinib in CD34(+) cells in diagnostic samples from two groups of patients distinguished by their cytogenetic response. No difference in inhibition of Crkl phosphorylation was observed in the two groups. The observation that increasing the dose of imatinib in vivo did not increase the level of cytogenetic response in some non-responders suggests that in at least a proportion of patients imatinib resistance may be due to activation of BCR-ABL1-independent pathway.
PMID: 19377081 [PubMed - indexed for MEDLINE]
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Administration of imatinib mesylate in patients with chronic myeloid leukemia with short bowel.
Leuk Lymphoma. 2009 Apr;50(4):670-2
Authors: Yamazaki R, Aisa Y, Mori T, Iketani O, Ikeda Y, Okamoto S
PMID: 19373671 [PubMed - indexed for MEDLINE]
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Presence of a new BCR-ABL kinase domain mutation, C330G in an imatinib naive patient with chronic myeloid leukemia: very low prevalence of BCR-ABL kinase domain mutations in patients with chronic myeloid leukemia from eastern India.
Leuk Lymphoma. 2009 Apr;50(4):663-6
Authors: Kuila N, Dash N, Sahoo DP, Pattnayak NC, Biswas G, Chakraborty S
PMID: 19373669 [PubMed - indexed for MEDLINE]
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Characterisation of extramedullary relapse in patients with chronic myeloid leukemia in advanced disease after allogeneic stem cell transplantation.
Leuk Lymphoma. 2009 Apr;50(4):551-8
Authors: Ocheni S, Iwanski GB, Schafhausen P, Zander AR, Ayuk F, Klyuchnikov E, Zabelina T, Fiedler W, Schnittger S, Hochhaus A, Brümmendorf TH, Kröger N, Bacher U
Recently, higher extramedullary relapse rates following allogeneic stem cell transplantation (SCT) in myeloid malignancies were reported e.g. because of selection of poor-risk patients. We analysed five consecutive patients with post-transplant extramedullary relapse of chronic myeloid leukemia (CML) out of a total of 24 patients (21%) undergoing allo-SCT. All five patients with extramedullary relapse had clonal evolution and a history of blast phase (BP). In particular, 56% of the patients in BP had extramedullary relapse with no extramedullary relapse in patients with chronic/accelerated phase. Most frequent manifestation sites were the skeletal system, the muscles/subcutaneous tissue and the central nervous system. In one case chloroma was mimicking myositis of the lower limbs. Combined approaches were performed including irradiation (n = 4), chemotherapy (n = 2), IM (n = 2), dasatinib (n = 4), nilotinib (n = 1), a novel aurora-kinase-inhibitor (n = 1), donor lymphocytes (n = 2) or a second allo-SCT (n = 2). Transient response was achieved in one case, stable partial remissions in two cases, whereas two cases were refractory. Research should focus on prospective studies aiming to improve treatment of extramedullary relapse in stem cell recipients with CML with a special focus on the role of second generation tyrosine kinase inhibitors.
PMID: 19373652 [PubMed - indexed for MEDLINE]
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Extramedullary relapse of chronic myeloid leukemia in blast crisis: more questions than answers.
Leuk Lymphoma. 2009 Apr;50(4):517-8
Authors: Ross DM
PMID: 19373644 [PubMed - indexed for MEDLINE]
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Posted by rob on September 24, 2009 under Uncategorized |
When Brian J. Druker was a boy, he wanted to be a baseball player; Nicholas B. Lydon had his sights set on flying jets; Charles L. Sawyers knew early on that he wanted to practice medicine. Decades later, this trio (Figure 1) would collaborate to revolutionize the treatment of chronic myelogenous leukemia (CML). On September 14, the Albert and Mary Lasker Foundation announced that they will recognize these researchers with the 2009 Lasker-DeBakey Clinical Medical Research Award for research that led to the development of drugs, including imatinib (Gleevec) and dasatinib (Sprycel), which have converted CML from a fatal cancer to a manageable condition. Notably, imatinib was the first successful, molecularly targeted, small-molecule drug approved for cancer therapy. The winners spoke with th…
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Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia.
Leukemia. 2009 Sep;23(9):1537-44
Authors: Cortes JE, Egorin MJ, Guilhot F, Molimard M, Mahon FX
Imatinib is the current standard of care in the treatment of chronic myeloid leukemia (CML), inducing durable responses and prolonged progression-free survival. However, plasma exposure to the drug from a given dosing regimen can vary widely among patients. Reasons for this may include incomplete adherence, intrinsic variations in the metabolism of imatinib, and drug-drug interactions. Data from two recent studies have shown a correlation between imatinib trough plasma concentration and clinical response, leading to suggestions that maintaining imatinib blood concentrations above approximately 1000 ng/ml might be associated with improved outcomes. In patients who do not respond as well as expected to initial imatinib treatment, measurement of trough plasma concentration could assist with decisions about whether to increase the dose. Blood-level testing may also be helpful in other clinical scenarios: for example, when poor adherence is suspected, adverse reactions are unusually severe, or there is a possible drug-drug interaction. Further work is required to confirm prospectively the link between imatinib plasma concentrations and response, and to define effective trough concentrations in different patient populations. However, based on the current data, imatinib blood-level testing seems to be a useful aid when making clinical decisions in CML.
PMID: 19404318 [PubMed - indexed for MEDLINE]
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The gatekeeper mutation T315I confers resistance against small molecules by increasing or restoring the ABL-kinase activity accompanied by aberrant transphosphorylation of endogenous BCR, even in loss-of-function mutants of BCR/ABL.
Leukemia. 2009 Sep;23(9):1614-21
Authors: Mian AA, Schüll M, Zhao Z, Oancea C, Hundertmark A, Beissert T, Ottmann OG, Ruthardt M
In Philadelphia chromosome-positive (Ph+) leukemia BCR/ABL induces the leukemic phenotype. Targeted inhibition of BCR/ABL by kinase inhibitors leads to complete remission. However, patients with advanced Ph+ leukemia relapse and acquire resistance, mainly due to point mutations in BCR/ABL. The ‘gatekeeper mutation’ T315I is responsible for a general resistance to small molecules. It seems not only to decrease the affinity for kinase inhibitors, but to also confer additional features to the leukemogenic potential of BCR/ABL. To determine the role of T315I in resistance to the inhibition of oligomerization and in the leukemogenic potential of BCR/ABL, we investigated its influence on loss-of-function mutants with regard to the capacity to mediate factor independence. Here, we show that T315I (i) requires autophosphorylation at tyrosine 177 in the BCR-portion to mediate resistance against the inhibition of oligomerization; (ii) restores the capacity to mediate factor-independent growth of loss-of-function mutants due to an increase in or activation of ABL-kinase; (iii) leads to phosphorylation of endogenous BCR, suggesting aberrant substrate activation by BCR/ABL harboring the T315I mutation. These data show that T315I confers additional leukemogenic activity to BCR/ABL, which might explain the clinical behavior of patients with BCR/ABL-T315I-positive blasts.
PMID: 19369965 [PubMed - indexed for MEDLINE]
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Posted by rob on September 23, 2009 under Uncategorized |
Synthesis of a 1,4-benzodiazepine containing palladacycle with in vitro anticancer and cathepsin B activity.
Dalton Trans. 2009 Jun 14;(22):4299-303
Authors: Spencer J, Rathnam RP, Motukuri M, Kotha AK, Richardson SC, Hazrati A, Hartley JA, Male L, Hursthouse MB
The reaction of the five-membered C,N-palladacycle [(L)PdCl](2), where LH = 1-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one, with 1,2-ethanebis(diphenylphosphine), dppe, leads to the formation of the bridged palladacycle. [Pd(2)L(2)(mu-dppe)Cl(2)] 3, which was characterised in solution by (1)H and (31)P NMR spectroscopy and in the solid state by X-ray crystallography. Complex 3 was tested in vitro against a number of cell lines. For example, it inhibited K562 leukaemia cells with an IC(50) value of 4.3 microM (1 h exposure) and displayed cathepsin B inhibitory action with an IC(50) value of 3 microM.
PMID: 19662306 [PubMed - indexed for MEDLINE]
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Identification and molecular characterization of recurrent genomic deletions on 7p12 in the IKZF1 gene in a large cohort of BCR-ABL1-positive acute lymphoblastic leukemia patients: on behalf of Gruppo Italiano Malattie Ematologiche dell’Adulto Acute Leukemia Working Party (GIMEMA AL WP).
Blood. 2009 Sep 3;114(10):2159-67
Authors: Iacobucci I, Storlazzi CT, Cilloni D, Lonetti A, Ottaviani E, Soverini S, Astolfi A, Chiaretti S, Vitale A, Messa F, Impera L, Baldazzi C, D’Addabbo P, Papayannidis C, Lonoce A, Colarossi S, Vignetti M, Piccaluga PP, Paolini S, Russo D, Pane F, Saglio G, Baccarani M, Foà R, Martinelli G
The BCR-ABL1 fusion gene defines the subgroup of acute lymphoblastic leukemia (ALL) with the worst clinical prognosis. To identify oncogenic lesions that combine with BCR-ABL1 to cause ALL, we used Affymetrix Genome-Wide Human SNP arrays (250K NspI and SNP 6.0), fluorescence in situ hybridization, and genomic polymerase chain reaction to study 106 cases of adult BCR-ABL1-positive ALL. The most frequent somatic copy number alteration was a focal deletion on 7p12 of IKZF1, which encodes the transcription factor Ikaros and was identified in 80 (75%) of 106 patients. Different patterns of deletions occurred, but the most frequent were those characterized by a loss of exons 4 through 7 (Delta4-7) and by removal of exons 2 through 7 (Delta2-7). A variable number of nucleotides (patient specific) were inserted at the conjunction and maintained with fidelity at the time of relapse. The extent of the Delta4-7 deletion correlated with the expression of a dominant-negative isoform with cytoplasmic localization and oncogenic activity, whereas the Delta2-7 deletion resulted in a transcript lacking the translation start site. The IKZF1 deletion also was identified in the progression of chronic myeloid leukemia to lymphoid blast crisis (66%) but never in myeloid blast crisis or chronic-phase chronic myeloid leukemia or in patients with acute myeloid leukemia. Known DNA sequences and structural features were mapped along the breakpoint cluster regions, including heptamer recombination signal sequences recognized by RAG enzymes during V(D)J recombination, suggesting that IKZF1 deletions could arise from aberrant RAG-mediated recombination.
PMID: 19589926 [PubMed - indexed for MEDLINE]
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Philadelphia-positive patients who already harbor imatinib-resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to second- or third-line tyrosine kinase inhibitors.
Blood. 2009 Sep 3;114(10):2168-71
Authors: Soverini S, Gnani A, Colarossi S, Castagnetti F, Abruzzese E, Paolini S, Merante S, Orlandi E, de Matteis S, Gozzini A, Iacobucci I, Palandri F, Gugliotta G, Papayannidis C, Poerio A, Amabile M, Cilloni D, Rosti G, Baccarani M, Martinelli G
Dasatinib and nilotinib are tyrosine kinase inhibitors (TKIs) developed to overcome imatinib resistance in Philadelphia-positive leukemias. To assess how Bcr-Abl kinase domain mutation status evolves during sequential therapy with these TKIs and which mutations may further develop and impair their efficacy, we monitored the mutation status of 95 imatinib-resistant patients before and during treatment with dasatinib and/or nilotinib as second or third TKI. We found that 83% of cases of relapse after an initial response are associated with emergence of newly acquired mutations. However, the spectra of mutants conferring resistance to dasatinib or nilotinib are small and nonoverlapping, except for T315I. Patients already harboring mutations had higher likelihood of relapse associated with development of further mutations compared with patients who did not harbor mutations (23 of 51 vs 8 of 44, respectively, for patients who relapsed on second TKI; 13 of 20 vs 1 of 6, respectively, for patients who relapsed on third TKI).
PMID: 19589924 [PubMed - indexed for MEDLINE]
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Long-term outcome of patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors after imatinib failure is predicted by the in vitro sensitivity of BCR-ABL kinase domain mutations.
Blood. 2009 Sep 3;114(10):2037-43
Authors: Jabbour E, Jones D, Kantarjian HM, O’Brien S, Tam C, Koller C, Burger JA, Borthakur G, Wierda WG, Cortes J
Secondary imatinib resistance in chronic myeloid leukemia (CML) is associated in approximately 50% of cases with mutations in the BCR-ABL kinase domain, necessitating switch to one of several new tyrosine kinase inhibitors (TKIs) that act differentially on mutated BCR-ABL. We assess here whether scoring mutation based on in vitro inhibitory concentration of each TKI-mutation pair can predict long-term clinical outcome. Among 169 patients with CML after imatinib failure, mutations were detected before TKI switch in 41 (48%) treated with dasatinib and 45 (52%) treated with nilotinib. Inhibitory concentration values for each TKI-mutation pair were stratified into high (n = 42), intermediate (n = 25), low (T315I, n = 9), or unknown sensitivity (n = 10). Hematologic and cytogenetic response rates were similar for patients with or without mutations. For patients in chronic phase, hematologic and cytogenetic responses correlated with mutation score; tumors with low and intermediate scores had lower response rates than those with highly sensitive mutations, and worse event-free and overall survival. These correlations with overall survival were not seen for advanced phases. Mutation scoring can predict outcome in CML-chronic phase with imatinib failure treated with second-generation TKIs and can help in therapy selection. More complex prognostic models will be required for advanced stages of disease.
PMID: 19567878 [PubMed - indexed for MEDLINE]
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Posted by rob on September 22, 2009 under Uncategorized |
Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy.
Leukemia. 2009 Aug;23(8):1398-405
Authors: Mustjoki S, Ekblom M, Arstila TP, Dybedal I, Epling-Burnette PK, Guilhot F, Hjorth-Hansen H, Höglund M, Kovanen P, Laurinolli T, Liesveld J, Paquette R, Pinilla-Ibarz J, Rauhala A, Shah N, Simonsson B, Sinisalo M, Steegmann JL, Stenke L, Porkka K
Dasatinib, a broad-spectrum tyrosine kinase inhibitor (TKI), predominantly targets BCR-ABL and SRC oncoproteins and also inhibits off-target kinases, which may result in unexpected drug responses. We identified 22 patients with marked lymphoproliferation in blood while on dasatinib therapy. Clonality and immunophenotype were analyzed and related clinical information was collected. An abrupt lymphocytosis (peak count range 4-20 x 10(9)/l) with large granular lymphocyte (LGL) morphology was observed after a median of 3 months from the start of therapy and it persisted throughout the therapy. Fifteen patients had a cytotoxic T-cell and seven patients had an NK-cell phenotype. All T-cell expansions were clonal. Adverse effects, such as colitis and pleuritis, were common (18 of 22 patients) and were preceded by LGL lymphocytosis. Accumulation of identical cytotoxic T cells was also detected in pleural effusion and colon biopsy samples. Responses to dasatinib were good and included complete, unexpectedly long-lasting remissions in patients with advanced leukemia. In a phase II clinical study on 46 Philadelphia chromosome-positive acute lymphoblastic leukemia, patients with lymphocytosis had superior survival compared with patients without lymphocytosis. By inhibiting immunoregulatory kinases, dasatinib may induce a reversible state of aberrant immune reactivity associated with good clinical responses and a distinct adverse effect profile.
PMID: 19295545 [PubMed - indexed for MEDLINE]
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Posted by rob on September 21, 2009 under Uncategorized |
Postmenopausal bleeding as first sign of an acute myelogenous leukaemia: A case report and review of the literature.
Med Oncol. 2009 Sep 10;
Authors: Henes M, Nauth A, Staebler A, Becker S, Henes JC
Postmenopausal bleeding (PMB) can have various causes and malignancy must always be excluded. Extramedullary manifestations of a haematological disease in the female genital tract are rare. We present the case of a woman with PMB as the first sign of an acute myelogenous leukaemia (AML). An 81-year-old patient presented with PMB. Manual and colposcopic examination raised suspicion of a cervical carcinoma, but histopathology and cervical Pap smear altered the diagnosis to granulocytic sarcoma (GS), an extramedullary manifestation of AML. The patient had a normal blood count 2 weeks prior to the examination, but at the time of presentation her leukocytes had risen to 116000/mul. The patient died 3 days later due to a pulmonary embolism, most probably as a result of leukostasis. In this case, GS of the cervix was the first sign of the AML with simultaneous appearance of leukocytosis and peripheral blasts. PMB was the reason for presentation. GS of the female genital tract is very rare and diagnosis is challenging, especially on the basis of the Pap smear. Abnormal inflammatory cells must be a warning sign and an indication for further examinations. GS as the presenting sign of AML has a poor prognosis with only 6% of patients surviving for more than 2 years.
PMID: 19763918 [PubMed - as supplied by publisher]
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Posted by rob on September 18, 2009 under Uncategorized |
We describe herein the case of a patient with chronic myelogenous leukemia (CML) accompanied by AvWS who was successfully treated with imatinib mesylate. (Source: Leukemia Research)
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Five scientists have won research awards for developing a lifesaving leukemia treatment and for advances in “reprogramming” DNA, which led to a new kind of stem cell. (Source: NYT > Health)
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Heat shock protein 90 – a potential target in the treatment of human acute myelogenous leukemia.
Curr Cancer Drug Targets. 2009 Sep;9(6):761-76
Authors: Reikvam H, Ersvaer E, Bruserud O
Heat shock proteins (HSPs) are molecular chaperones that stabilize folding and conformation of normal as well as oncogenic proteins. These chaperones thereby prevent the formation of protein aggregates. HSPs are often overexpressed in human malignancies, including AML. HSP90 is the main chaperon required for the stabilization of multiple oncogenic kinases involved in the development of acute myelogenous leukemia (AML). HSP90 client proteins are involved in the regulation of apoptosis, proliferation, autophagy and cell cycle progression; several of these proteins are in addition considered as possible therapeutic targets for the treatment of AML. HSP90 inhibition thereby offers the possibility to modulate several intracellular regulatory pathways through targeting of a single molecule. Several direct inhibitors of HSP90 have been developed, and they are classified into four groups: benzoquinon ansamycines and their derivatives, radicicol and its derivates, small synthetic inhibitors and a final group of other inhibitors. The HSP90 activity is regulated by posttranscriptional modulation; HSP90 inhibition can thereby be indirectly achieved through increased acetylation caused by histone deacetylase inhibitors. Many of these agents have entered phase I/II clinical trials, and the results from these initial studies have documented that HSP90 inhibition can mediate antileukemic effects in vivo. However, one would expect immunosuppressive side effects because HSP90 inhibitors have both direct and indirect inhibitory effects on T cell activation. Thus, future clinical studies are needed to clarify the efficiency and toxicity of HSP90 inhibitors in the treatment of human AML, including studies where HSP90 inhibitors are combined with conventional chemotherapy.
PMID: 19754360 [PubMed - in process]
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Sorting Cancer Karyotypes by Elementary Operations.
J Comput Biol. 2009 Sep 15;
Authors: Ozery-Flato M, Shamir R
Abstract Since the discovery of the “Philadelphia chromosome” in chronic myelogenous leukemia in 1960, there has been ongoing intensive research of chromosomal aberrations in cancer. These aberrations, which result in abnormally structured genomes, became a hallmark of cancer. Many studies provide evidence for the connection between chromosomal alterations and aberrant genes involved in the carcinogenesis process. An important problem in the analysis of cancer genomes is inferring the history of events leading to the observed aberrations. Cancer genomes are usually described in the form of karyotypes, which present the global changes in the genomes’ structure. In this study, we propose a mathematical framework for analyzing chromosomal aberrations in cancer karyotypes. We introduce the problem of sorting karyotypes by elementary operations, which seeks a shortest sequence of elementary chromosomal events transforming a normal karyotype into a given (abnormal) cancerous karyotype. Under certain assumptions, we prove a lower bound for the elementary distance, and present a polynomial-time 3-approximation algorithm for the problem. We applied our algorithm to karyotypes from the Mitelman database, which records cancer karyotypes reported in the scientific literature. Approximately 94% of the karyotypes in the database, totaling 58,464 karyotypes, supported our assumptions, and each of them was subjected to our algorithm. Remarkably, even though the algorithm is only guaranteed to generate a 3-approximation, it produced a sequence whose length matched the lower bound (and hence optimal) in 99.9% of the tested karyotypes.
PMID: 19754273 [PubMed - as supplied by publisher]
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Significance of suboptimal response to imatinib, as defined by the European LeukemiaNet, in the long-term outcome of patients with early chronic myeloid leukemia in chronic phase.
Cancer. 2009 Aug 15;115(16):3709-18
Authors: Alvarado Y, Kantarjian H, O’Brien S, Faderl S, Borthakur G, Burger J, Wierda W, Garcia-Manero G, Shan J, Cortes J
BACKGROUND: The European LeukemiaNet recommendations for chronic myeloid leukemia (CML) defined a group of patients with suboptimal response to imatinib. The significance of this response was not well defined. METHODS: The significance of having had a suboptimal response during imatinib therapy among 281 patients with CML treated with standard-dose (n = 73) or high-dose (n = 208) imatinib was investigated. RESULTS: Rates of suboptimal response at 6, 12, and 18 months were 4%, 8%, and 40%, respectively, and were not influenced by Sokal risk score. Patients with a suboptimal response at 6 months had a significantly lower probability of eventually achieving a complete cytogenetic response (CCyR) compared with those with an optimal response (30% vs 97%; P < .001), and their event-free survival (EFS) and transformation-free survival (TFS) were found to be similar to those with criteria for failure at this time point. Suboptimal response at 12 months defined a group with a similar TFS as those with optimal response, but with worse EFS. In contrast, patients with a suboptimal response at 18 months had outcomes that were similar to those patients with an optimal response. A multivariate analysis confirmed the significance of response category after adjusting for pretreatment characteristics and imatinib dose. CONCLUSIONS: The results of the current study suggested that suboptimal response was a heterogeneous category, and some patients had an outcome that mirrored that of patients with failed therapy. Interventions aimed at improving this outcome are required.
PMID: 19517462 [PubMed - indexed for MEDLINE]
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Kinase drug discovery approaches in chronic myeloproliferative disorders.
Oncogene. 2009 Jun 18;28(24):2305-13
Authors: Kumar C, Purandare AV, Lee FY, Lorenzi MV
Myeloproliferative disorders (MPDs) are clonal malignancies that arise from hematopoietic progenitors and characterized by overproduction of mature, functional blood cells. These disorders can be broadly characterized into Philadelphia chromosome-positive (Ph(+)) or negative (Ph(-)) genetic groupings. Chronic myeloid leukemia (CML) is a Ph(+) MPD that is defined on the basis of its molecular lesion, the BCR-ABL fusion gene. Inhibitors directed at the constitutive kinase activity of BCR-ABL have been shown to be disease modifying in CML and have dramatically altered the standard of care for this leukemia. The three main Ph(-) MPDs are polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The key features of these Ph(-) MPDs are an increased red blood cell mass in PV, a high platelet count in ET and bone marrow fibrosis in PMF, respectively. These disorders also share many clinical features such as long clinical course, increased risk for thrombosis, hemorrhage and elevated risk of leukemic transformation. Interest in these disorders has been ignited by the recent discovery of activating mutations in the tyrosine kinase gene, JAK2, in the predominance of Ph(-) MPD patients and has highlighted JAK2 as a therapeutic intervention point for drug discovery efforts with selective kinase inhibitors. This review will focus on the comparison of Ph(+) and Ph(-) MPDs, drug discovery and development efforts targeting these disorders, and will assess the new opportunities for targeted therapies for these diseases.
PMID: 19421140 [PubMed - indexed for MEDLINE]
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