Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ETV6/ABL1 (TEL/ABL) fusion gene is a rare aberration in malignant disorders. Only 19 cases of ETV6/ABL1-positive hematological malignancy have been published, diagnosed with chronic myeloid leukemia, other types of chronic myeloproliferative neoplasm, acute myeloid leukemia or acute lymphoblastic leukemia (ALL). This study reports three new cases (aged 8 months, 5 years, and 33 years) of ALL with the ETV6/ABL1 fusion found by screening 392 newly diagnosed ALL patients (335 children and 57 adults). A thorough review of the literature and an analysis of all published data, including the three new cases, suggest poor prognosis of ETV6/ABL1-positive acute leukemias. The course of the disease in the two pediatric patients is characterized by minimal residual disease monitoring, using quantification of both the ETV6/ABL1 transcript and immunoreceptor gene rearrangements. Eosinophilia could not be confirmed as a hallmark of the ETV6/ABL1-positive disease. Studies of neonatal blood spots demonstrated that, in the child diagnosed at five years, the ETV6/ABL1 fusion initiating the ALL originated prenatally.
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PMID:Acute leukemias with ETV6/ABL1 (TEL/ABL) fusion: poor prognosis and prenatal origin. 2058 32

Myeloproliferation with prominent eosinophilia is associated with rearrangements of PDGFR-A or -B. The most common rearrangement is FIP1L1-PDGFRA (FP). The majority of patients with PDGFR-rearranged myeloproliferation respond to treatment with imatinib. In contrast to BCR-ABL-positive chronic myelogenous leukemia, only few cases of imatinib resistance and mutations of the FP kinase domain have been described so far. We hypothesized that the number of critical residues mediating imatinib resistance in FP in contrast to BCR-ABL might be limited. We performed an established systematic and comprehensive in vitro resistance screen to determine the pattern and frequency of possible TKI resistance mutations in FP. We identified 27 different FP kinase domain mutations including 25 novel variants, which attenuated response to imatinib, nilotinib or sorafenib. However, the majority of these exchanges did not confer complete inhibitor resistance. At clinically achievable drug concentrations, FP/T674I predominated with imatinib, whereas with nilotinib and sorafenib, FP/D842V and the compound mutation T674I+T874I became prevalent. Our results suggest that the PDGFR kinase domain contains a limited number of residues where exchanges critically interfere with binding of and inhibition by available PDGFR kinase inhibitors at achievable concentrations, which might explain the low frequency of imatinib resistance in this patient population. In addition, these findings would help to select the appropriate second-line drug in cases of imatinib-resistant disease and may be translated to other neoplasms driven by activated forms of PDGFR-A or -B.
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PMID:The low frequency of clinical resistance to PDGFR inhibitors in myeloid neoplasms with abnormalities of PDGFRA might be related to the limited repertoire of possible PDGFRA kinase domain mutations in vitro. 2097 53

Systemic mastocytosis (SM) is a heterogeneous disease, vast majority of these patients have a gain of function mutation in the gene encoding the tyrosine kinase KIT (KIT(D816V)). A small subset of SM patients with KIT(D816V) mutation require cytoreductive therapy. In these patients, tyrosine kinase inhibitors (TKIs) have been actively investigated over the last decade because of codon 816 KIT mutations causing constitutive activation of tyrosine kinase activity of the molecule. The main question has been whether the success story with imatinib in chronic myeloid leukemia (CML), another disease associated with a constitutively active tyrosine kinase, could be mimicked in mastocytosis. However, the results from various TKIs in SM with KIT(D816V) mutation have been disappointing to date. Only a few of the TKIs sufficiently block KIT(D816V) activity and have shown promising clinical results. The data from these studies indicate that, apart from KIT(D816V), other kinase targets and target pathways may play a role in disease evolution and progression, especially in patients with SM with an associated clonal hematological non-mast cell lineage disease (SM-AHNMD). Imatinib is effective in patients with increased mast cells and eosinophils associated with FIP1L1/PDGFRA+ (e.g., myeloid neoplasm with eosinophilia and rearrangement of PDGFRA) or rare patients with SM associated with KIT mutations outside of exon 17. This review will focus on the KIT receptor, KIT mutations, and the effects of the mutations in SM. The preclinical and clinical activities of FDA approved TKIs (for CML) as well as novel TKIs in SM will be evaluated.
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PMID:Tyrosine kinase inhibitors in the treatment of systemic mastocytosis. 2164 42

As well as playing vital roles in main cellular processes, such as abnormal proliferation, differentiation, survival, apoptosis, and a lot of tyrosine kinases (TK) are involved in oncogenesis. TK or components of their signal pathways have been found abnormal in many hematological malignancies. Therefore, tyrosine kinase inhibitors (TKI) have been provided a great deal of enthusiasm for development of therapy in myeloproliferative neoplasms (MPN). Representativity, the treatment of chronic myelogenous leukemia (CML) was revolutionary for the design of imatinib mesylate (IM), which is a BCR/ABL TKI. Subsequently, because of need for the resistance or intolerance, novel agents are being explored and imatinib has now been extended to eosinophilia-associated myeloid neoplasms with PDGFRA, PDGFRB or FGFR1 gene mutations. Recently, JAK2 inhibitor drugs are currently being tested in clinical trials. Here, the current review mainly focuses on the role of TK in classic MPN including CML, polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET), and advances of targeting these abnormalities with small molecule inhibitors.
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PMID:Application of tyrosine kinase inhibitors as a promising targeting treatment for myeloproliferative neoplasms --- review. 2186 45

Chronic basophilic leukemia is a rare form in chronic myeloid leukemia patients. Only limited number of reports are available. Herein, we describe a patient who presented with fatigue, weight loss, leucocytosis, prominent basophilia, and mild eosinophilia. On biopsy, bone marrow was hypercellular with marked basophils. The immunophenotype showed abnormal expression of CD7, which is suggestive of basophilic maturation. Chromosomal analysis from GTG-banded metaphases revealed Ph positivity, and fluorescence in situ hybridization (FISH) with BCR/ABL dual color, dual fusion probe showed single fusion on the der(22) chromosome and ABL/BCR fusion was deleted on the der(9) chromosome. The deletion (ABL/BCR) on der(9) may be associated with basophilia which may be also indicative of the transformation of CML to acute myeloid leukemia.
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PMID:Deletion of ABL/BCR on der(9) associated with severe basophilia. 2209 Jul 23

Hypereosinophilic syndrome (HES) and the association of hypereosinophilia with acute lymphoblastic leukaemia (ALL) are both rare in children. Some acute myelogenous leukaemias can present with eosinophilia, but the relationship between HES and ALL is not well known and is rarer than the relationship between HES and acute myelogenous leukaemia. Patients are diagnosed with HES when no cause is found to explain the eosinophilia leading to end organ damage. For this reason, it is recommended that patients presenting with hypereosinophilia be carefully assessed to exclude any malignant clonal proliferation. HES may present with severe clinical manifestations such as high leucocyte count, anaemia, thrombocytopaenia, hepatosplenomegaly or cardiac and neurological involvement, all of which are primarily features of myeloproliferative disorders. Some patients with HES can develop chronic eosinophilic leukaemia. Successful treatment of HES with agents used in chronic myeloid leukaemia supports the idea that HES can be a chronic myeloid disorder. There are few cases reporting an association between ALL and hypereosinophilia that precedes or is concomitant with ALL. Here we report the case of a 14-year-old girl who developed common B ALL 7 months after diagnosis and treatment of HES. Interestingly, eosinophilia was not concomitant with the diagnosis of ALL.
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PMID:Does hypereosinophilic syndrome precede common B acute lymphoblastic leukaemia in childhood? A case report. 2215 91

There is no single category in the fourth edition (2008) of the World Health Organization (WHO) classification of myeloid neoplasms that encompasses all of the diseases referred to by some authors as the myeloproliferative neoplasm (MPN) "variants." Instead, they are considered as distinct entities and are distributed among various subgroups of myeloid neoplasms in the classification scheme. These relatively uncommon neoplasms do not meet the criteria for any so-called "classical" MPN (chronic myelogenous leukemia, polycythemia vera, primary myelofibrosis, or essential thrombocythemia) and, although some exhibit myelodysplasia, none meets the criteria for any myelodysplastic syndrome (MDS). They are a diverse group of neoplasms ranging from fairly well-characterized disorders such as chronic myelomonocytic leukemia to rare and thus poorly characterized disorders such as chronic neutrophilic leukemia. Recently, however, there has been a surge of information regarding the genetic infrastructure of neoplastic cells in the MPN variants, allowing some to be molecularly defined. Nevertheless, in most cases, correlation of clinical, genetic, and morphologic findings is required for diagnosis and classification. The fourth edition of the WHO classification provides a framework to incorporate those neoplasms in which a genetic abnormality is a major defining criterion of the disease, such as those associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1, as well as for those in which no specific genetic defect has yet been discovered and which remain clinically and pathologically defined. An understanding of the clinical, morphologic, and genetic features of the MPN variants will facilitate their diagnosis.
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PMID:World health organization classification, evaluation, and genetics of the myeloproliferative neoplasm variants. 2216 42

Acute myeloid leukemia (AML) is a phenotypically heterogeneous disorder. The M4 subtype of AML is frequently associated with the cytogenetic marker inversion 16 and/or the presence of eosinophilia. Blast crisis is the aggressive phase of the triphasic chronic myeloid leukemia (CML), which is a disease with Philadelphia(Ph) chromosome as the major abnormality. In the present study, we report a 76-year-old patient suspected of having AML with eosinophilic differentiation (AML-M4), which in clinical tests resembles CML blast crisis with multiple chromosomal abnormalities. Isochromosome 21 [i(21)(q10)] was the most recurrent feature noted in metaphases with 46 chromosomes. Ring chromosome, tetraploid endoreduplication, recurrent aneuploid clones with loss of X chromosome, monosomy 17, monosomy 7, and structural variation translocation (9;14) were also observed in this patient. Fluorescent in situ hybridization (FISH) confirmed the absence of Ph chromosome. This report shows how cytogenetic analyses revealed atypical structural aberrations in the M4 subtype of AML.
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PMID:Recurrent isochromosome 21 and multiple abnormalities in a patient suspected of having acute myeloid leukemia with eosinophilic differentiation -- a rare case from South India. 2217 74

The occurrence of chronic myeloid leukaemia (CML) in patients infected with the human immunodeficiency virus (HIV) has rarely been reported in the literature. In this report, we describe the experience of a single centre in the management of 10 such patients, including demographic information, disease characteristics and response to therapy. We had a black female predominance in our series, with only a minority of patients achieving a complete cytogenetic response. The main reason for this appears to be compliance, which was influenced by distance to the treating centre. The side-effect profile was similar to that expected, with the exception of one patient who developed a drug rash with eosinophilia and systemic symptoms. Although CML patients co-morbid for HIV face certain unique challenges when compared to non-infected patients, their long-term outcome can be positive when appropriately managed.
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PMID:Chronic myeloid leukaemia and human immunodeficiency virus (HIV) infection. 2252 50

An 8-year-old male neutered Labrador Retriever was referred to the University of Wisconsin Veterinary Medical Teaching Hospital with a presumptive diagnosis of leukemia. Hematologic abnormalities included normal neutrophil count with a left shift, monocytosis, eosinophilia, thrombocytopenia, and circulating immature mononuclear cells. Bone marrow was effaced by immature hematopoietic cells of various morphologic appearances. In addition, large multinucleated cells were observed frequently. Flow cytometric analysis of nucleated cells in blood revealed 34% CD34(+) cells, consistent with acute leukemia. By immunocytochemical analysis of cells in blood and bone marrow, some mononuclear cells expressed CD18, myeloperoxidase, and CD11b, indicating myeloid origin; some, but not all, large multinucleated cells expressed CD117 and CD42b, the latter supporting megakaryocytic lineage. The diagnosis was acute myeloblastic leukemia without maturation (AML-M1). To identify genetic aberrations associated with this malignancy, cells from formalin-fixed paraffin-embedded bone marrow were analyzed cytogenetically by multicolor fluorescence in situ hybridization (FISH). Co-localization of bacterial artificial chromosome (BAC) containing BCR and ABL was evident in 32% of cells. This confirmed the presence of the canine BCR-ABL translocation or Raleigh chromosome. In people, the analogous translocation or Philadelphia chromosome is characteristic of chronic myelogenous leukemia (CML) and is rarely reported in AML. BCR-ABL translocation also has been identified in dogs with CML; however, to our knowledge this is the first report of AML with a BCR-ABL translocation in a domestic animal.
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PMID:Acute myeloblastic leukemia with associated BCR-ABL translocation in a dog. 2274 55


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