A Novel and Cytogenetically Cryptic t(7;21)(q36.1;q22) Disrupting RUNX1 in Acute Myeloid Leukemia.

Translocations involving the RUNX1 transcription factor gene are frequently identified in leukemia patients, but the partner genes have been characterized in only about half of these cases. We report here a novel RUNX1 partner gene, KMT2C (MLL3), in a patient with de novo acute myeloid leukemia, having a novel and cytogenetically cryptic t(7;21)(q36.1;q22) leading to disruption of RUNX1 and KMT2C. This is the third cryptic RUNX1 rearrangement in myeloid and the fourth in hematologic malignancies.

Novel approaches to the development of tyrosine kinase inhibitors and their role in the fight against cancer.

INTRODUCTION: Protein tyrosine kinase inhibitors are currently one of the most important classes of cancer drugs and one of the most impressive approaches of targeted cancer therapy. Aberrant activation of tyrosine kinase pathways is among the most dysregulated molecular pathways in human cancers; therefore, a large number of tyrosine kinases may serve as valuable molecular targets. To date, several inhibitors of tyrosine kinases have been approved and there are hundreds more compounds that are in various stages of development. Because of the deregulation in human malignancies, the ABL1, SRC, the epidermal growth factor receptor and the vascular endothelial growth factor receptor kinases are among the protein kinases that are considered as prime molecular targets for selective inhibition. AREAS COVERED: This review focuses on most important small-molecule inhibitors that serve as a model for future development. They also provide a broad overview of some of the new approaches and challenges in the field. EXPERT OPINION: With the exception of a few malignancies seemingly driven by a limited number of genetic lesions, current targeted therapeutic approaches have shown only limited efficacy in advanced cancers. Consequently, more sophisticated strategies, such as identification of pathogenic 'driver' mutations and optimization of personalized therapies are needed.

Unusual location of BCR-ABL1 fusion sequences in a chronic myeloid leukemia patient.

We describe a case of a chronic myeloid leukemia patient displaying the chimeric BCR-ABL1 gene on 12p11. Chromosome analysis revealed complex chromosome aberration involving chromosomes 9, 12, and 22. Fluorescence in situ hybridization revealed an unusual signal pattern revealing the BCR-ABL1 fusion signal on chromosome 12, while no reciprocal ABL1-BCR fusion was detected on der(9) chromosome. The relocation of BCR-ABL1 fusion sequences to 12p11 site in our patient represents a rare type of variant translocation, as in almost all patients the chimeric BCR-ABL1 gene is located on der(22) chromosome. Our case illustrates the challenge of recognizing a complex pattern of cytogenetic aberrations that occur with variant t(9;22) and may add further information about clinical significance of unusual variant Ph rearrangements in CML patients receiving tyrosine kinase inhibitor treatment.

Probable asociación de los inhibidores de la tirosina quinasa con la persistencia de clones aberrantes con cromosoma Filadelfia negativo / Probable association of tyrosine kinase inhibitors with aberrant clones persistent Philadelphia chromosome negative

Paciente de 43 años diagnosticado con leucemia mieloide crónica en 1998, que fue tratado de forma inicial con interferón alfa. En la terapia posterior adquirió múltiples cambios citogenéticos clonales en células del cromosoma Filadelfia negativas, por lo que se describe el efecto de los inhibidores de la tirosina quinasa de segunda generación sobre esos clones celulares.

Targeting the BCR-ABL tyrosine kinase in chronic myeloid leukemia as a model of rational drug design in cancer.

Many biological and clinical features of chronic myeloid leukemia make it as a paradigm of rational drug design in human cancer. Chronic myeloid leukemia was the first malignancy to be linked to a clear genetic anomaly, the Philadelphia chromosome and, at present, it is probably the best understood of all human malignancies. Studies of the disease pathology revealed that the molecular consequence of the Philadelphia translocation is a BCR-ABL chimeric gene, which encodes a constitutively active tyrosine kinase with wholesale range of biological activities. Animal models have validated the direct role of the BCR-ABL protein in malignant transformation and subsequent research confirmed that its enhanced tyrosine kinase activity is essential and sufficient for the leukemogenesis. The very existence of a single genetic abnormality, presented in essentially all patients with the disease, made it an effective target for molecularly designed therapeutic approaches for the disease. The advent of tyrosine kinase inhibitors, designed specifically to inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein, represents one of the major innovations in cancer therapy and may serve as a model for, how discoveries of disease pathogenesis may be translated into the development of successful targeted therapies in cancer medicine.

Frequency and type of chromosomal abnormalities in childhood acute lymphoblastic leukemia patients in Kuwait: a six-year retrospective study.

OBJECTIVE: To characterize the frequency of genetic profiles in pediatric acute lymphoblastic leukemia (ALL) patients in Kuwait. SUBJECTS AND METHODS: This review presents the general cytogenetic characteristics of 164 pediatric patients diagnosed as having ALL in a 6-year period. Chromosomal and fluorescence in situ hybridization studies were made on bone marrow aspirates at diagnosis and during different stages of the disease. RESULTS: Recurring aberrations, observed in 123 (75%) patients, included hyperdiploidy (n=68, 41%), tetraploidy (n=12, 7.3%), hypodiploidy (n=2, 1.2%), TEL-AML1 fusion (n=11, 7%), mixed-lineage leukemia rearrangement (n=6, 3.6%), t(9;22) (n=4, 2.4%), t(1;19) (n=3, 1.8%), t(8;14) or t(8;22) (n=2, 1.2%), +21 (n=2, 1.2%), del(6) (n=2, 1.2%) and miscellaneous abnormalities (n=9, 5%). The highest observed numerical chromosome abnormality was high hyperdiploidy in 89 patients (54%) with abnormal karyotype while the TEL-AML fusion was the highest observed structural abnormality. CONCLUSION: This study showed that clonal anomalies detected in pediatric ALL have shown correlations between specific abnormalities and clinicobiological characteristics of the patients.

Genomic instability and rapid clinical course in adult T-cell lymphoma/leukemia patient.

Adult T-cell leukemia/lymphoma is a distinct clinical entity characterized by a clonal proliferation of malignant T-lymphocytes. The etiologic agent of the disease is a Human T-cell lymphotropic virus type I. It occurs almost exclusively in areas where the virus is endemic; however the disease develops only in the minority of patients who are virus carriers. Karyotyping findings and their correlation with clinical features are still limited in T-cell malignancies, complicated by clinical heterogeneity and a plethora of secondary abnormalities. This study describes detailed chromosomal and fluorescence in situ hybridization results observed in a patient with adult T-cell leukemia/lymphoma and correlates them with clinical characteristics.

Simultaneous occurrence of MLL and RARA rearrangements in a pediatric acute lymphoblastic leukemia patient.

We report a case of concurrent translocations of MLL gene, associated with a highly distinct leukemia subtype and RARA gene, which is pathogenomic in acute promyelocytic leukemia. Conventional cytogenetic revealed a novel complex rearrangement between chromosomes 5, 11, and 17 resulting in a three-way chromosome translocation t(5;11;17)(q31;q23;q21). Fluorescence in situ hybridization analysis demonstrated that the 11q23 breakpoint involved the MLL, and the 17q21 breakpoint involved the RARA gene. Concurrent translocations of two specific oncogenes MLL and RARA with a new partner breakpoint on 5q31 have not been previously described.

Simultaneous occurrence of t(9;22)(q34;q11.2) and t(16;16)(p13;q22) in a patient with chronic myeloid leukemia in blastic phase.

Coexistence of two specific chromosomal translocations in the same clone is an infrequent phenomenon and has only rarely been reported in hematological malignancies. We report a combination of t(16;16)(p13;q22), the Philadelphia translocation t(9;22)(q34;q11.2), and deletion of the long arm of chromosome 7 in a patient with chronic myeloid leukemia in blast phase. Monotherapy treatment with imatinib mesylate resulted in the disappearance of the Ph-positive clone, but with persistence of t(16;16) and del(7) in all of the metaphases examined. The case illustrates that, although imatinib mesylate can be an effective treatment in eradication of the BCR-ABL fusion gene cells, the occurrence of additional specific abnormalities in Philadelphia-positive leukemias may pose a significant therapeutic challenge.

Trisomy 6 in a CML patient receiving imatinib mesylate therapy.

The emergence of chromosome abnormalities in Philadelphia-negative cells in chronic myelogenous leukemia patients during imatinib therapy have been described by several authors. While these abnormalities are frequently transient, in rare instances they may be presented on repeated occasions suggesting the possibility of the development of a new malignant clone. We describe a patient with Philadelphia chromosome-positive chronic myelogenous leukemia diagnosed in 1998, in whom multiple clonal abnormalities were identified in Ph-negative cells while on imatinib therapy. The patient developed lymphoid blast crisis associated with an additional Ph chromosome and trisomy 6 in Ph-negative cells. Our results further reinforce the importance of serial chromosomal studies in patients receiving new therapies which may ultimately lead to alternative therapies.

Establishment and characterization of a new lung cancer cell line (MI-4) producing high levels of granulocyte colony stimulating factor.

We established a human lung cancer cell line, MI-4 from the pleural effusion of a 69-year-old male with advanced large cell undifferentiated carcinoma of the lung complicated by leukocytosis. The culture supernatant of MI-4 contained high levels of granulocyte colony stimulating factor (G-CSF). The intracellular localization of the G-CSF was identified by immunocytochemistry. Reverse transcription-polymerase chain reaction (RT-PCR) revealed G-CSF mRNA expression in this cell line. The cell line was successfully transplanted into nude mice. The transplanted nude mice also showed leukocytosis with a high serum G-CSF level. Southern blot analysis did not show amplification or rearrangement of the G-CSF gene in MI-4 cells. Spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) analyses revealed that this cell line has an additional chromosome 17 attached to a segment of chromosome 10 besides two intact chromosomes 17, and that each of these three chromosomes 17 has a G-CSF gene on chromosome 17q. Inflammatory cytokines, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta, significantly enhanced G-CSF expression at both the protein and mRNA levels in MI-4. However, these cytokines did not stimulate the growth of MI-4 cells, regardless of abundant G-CSF production. TNF-alpha rather suppressed it, in a dose-dependent manner. Exogenous recombinant human G-CSF and anti-G-CSF antibody did not promote or inhibit the growth of MI-4 cells at any concentration examined. In addition, RT-PCR analysis did not show G-CSF receptor mRNA expression. These results suggest that this cell line does not have an autocrine growth loop for G-CSF. This cell line should be very useful for understanding the biological activity of G-CSF in G-CSF-overproducing lung cancer.

Coexistence of Philadelphia-positive chronic granulocytic leukemia and diffuse large B-cell lymphoma at initial diagnosis.

We describe the rare coexistence at the time of diagnosis of Philadelphia positive chronic myelogenous leukemia (Ph+ CML) and non-Hodgkin's lymphoma (NHL). At the time of diagnosis, cytogenetic analysis of peripheral blood and bone marrow cells revealed the Ph chromosome translocation in all examined metaphases. The lymph node biopsy showed features of diffuse large B-cell lymphoma (DLBCL). This case may be of interest due to: (1) the rare coexistence of Ph+ CML and NHL at diagnosis, (2) the fact, that in contrary with previously reported cases in patients with antecedent or concurrent diagnosis of CML, where precursor lymphoblastic lymphomas are prevalent, in our patient clinical and laboratory findings revealed a diffuse large B-cell lymphoma, and (3) that the present case is an additional one confirming the poor outcome of patients with simultaneous occurrence of these two clinical entities.