Signicance of Philadelphia Chromosome in Chronic Myeloid Leukemia Patients of Anmol Hospital, Lahore, Pakistan

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Kanwal Rashid ◽  
Amber Hassan ◽  
Imrana Tanvir ◽  
Kashifa Ehsan
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Experimental Studies ◽  
Chromosome 8 ◽  
Myelogenous Leukemia ◽  
Chromosomal Marker ◽  
Rt Pcr ◽  
Ph Chromosome ◽  
Cell Disorder

Chronic myelogenous Leukemia is (Clonal stem cell disorder) cancer which starts in bone marrow a soft tissue inside bones that aids to form blood cells. It is rst form of cancer that was rstly recognize to associate strongly with the chromosomal abnormality and the chromosome [t (9; 22) translocation] called Philadelphia chromosome. Abstract: Objective: Philadelphia chromosome is a characteristic chromosomal marker that is associated with chronic myelogenous leukemia. Methods: More than one hundred patients of either sex were selected for the experiment. RNA was isolated from whole blood of patients so can use exclusively in RT-PCR. Results: Philadelphia chromosome in blood samples of patients with suspected diagnosis of CML was detected in 63% of patients. During our experimental studies on CML patients we do not encounter any complex translocation involving chromosome 8, 9 and 22. Conclusions: Philadelphia chromosome is a precise cytogenetic marker the detection of which is signicant for differential diagnosis and clinical organization of patients with clinical diagnosis of CML. It is of signicant that Ph chromosome occurs in pre-leukemic stage and has great diagnostic signicance.

scholarly journals Human chronic myelogenous leukemia cell-line with positive Philadelphia chromosome

Blood ◽  
1975 ◽  
Vol 45 (3) ◽  
pp. 321-334 ◽  
Author(s):  
CB Lozzio ◽  
BB Lozzio
Keyword(s):  
Cell Line ◽  
Chronic Myelogenous Leukemia ◽  
Culture Media ◽  
Specific Antigen ◽  
Philadelphia Chromosome ◽  
Experimental Studies ◽  
Leukemia Cell ◽  
Myelogenous Leukemia ◽  
Chromosome 17 ◽  
Leukemia Cell Line

Abstract A cell-line derived from a patient with chronic myelogenous leukemia (CML) is described. The new cell-line, which has over 175 serial passanges in a 3 1/2-yr period, has the following characteristics: (1) CML cells started to proliferate actively since they were first incubated in culture media. A threefold increase in the total number of cells was observed during the first seven passages; the cell population increased by a factor of 10 to 20 every 7 days from passage 8 through 85; from 20 to 40 times from passage 86 through 150, and more than 40 times after 150 passages. (2) The majority of the nononucleated cells are undifferentiated blasts. (3) The karyotype of all the cells examined show the Philadelphia (Ph1) chromosome and a long acrocentric marker plus aneuploidy. The Giemsa-banding studies identified the Ph1 chromosome as a terminal deletion of the long arm of chromosome 22:del(22)(q12) and the long acrocentric marker as an unbalanced reciprocal translocation of one chromosome 17 and the long arm of one chromosome 15. (4) The CML cells do not produce immunoglobulins, are free of mycoplasma, Epstein-Barr virus, and herpes-like virus particles. (5) CML cells have no alkaline phosphatase and myeloperoxidase activities and did not engulf inert particles. (6) Cultured CML cells provide a constant source of a specific antigen. This CML cell-line represents a unique source of CML cells with meaningful indicators of malignancy for clinical and experimental studies.

Once-Daily Dasatinib for Treatment of Patients with Chronic Myeloid Leukemia

2009 ◽  
Vol 43 (5) ◽  
pp. 920-927 ◽  
Author(s):  
Timothy Tyler
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Chronic Myelogenous Leukemia ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Once Daily ◽  
Number Of Patients ◽  
Significant Difference ◽  
American Society

Objective To discuss the new dasatinib dosing regimen for the treatment of chronic phase chronic myelogenous leukemia (CP CML) in patients who failed or were intolerant to imatinib therapy. Data Sources Literature published between July 2008 and December 2008 was accessed via MEDLINE, the Proceedings of the American Society of Hematology, and the Proceedings of the American Society of Clinical Oncology using the key words chronic myelogenous leukemia, chronic myeloid leukemia, dasatinib, imatinib, nilotinib, pharmacokinetics, and regimen. Study Selection And Data Extraction Meeting abstracts and reports of major Phase 1–3 studies published in English are included. Data Synthesis Imatinib is the standard first-line therapy for CML; however, some patients develop resistance or are intolerant to the drug. Dasatinib was approved for the treatment of imatinib-resistant/intolerant patients with CML or Philadelphia chromosome–positive acute lymphoblastic leukemia at the dosage of 70 mg twice daily. A Phase 3 dose-optimization study was performed to compare this regimen with others, including dasatinib 100 mg once daily, in patients with CP CML. Results of this study showed that there was no significant difference in efficacy between these 2 regimens. The safety profile was improved in the 100-mg once-daily dasatinib arm with significantly reduced frequencies of grade 3–4 thrombocytopenia and all-grade pleural effusions. The number of patients who had to discontinue, reduce, or interrupt their dosage was also less among patients taking dasatinib 100 mg once daily. Conclusions Dasatinib 100 mg once daily has a more favorable risk to benefit assessment compared with the previous 70 mg twice-daily regimen and is now the recommended schedule for patients with CP CML.

scholarly journals Detection of two alternative bcr/abl mRNA junctions and minimal residual disease in Philadelphia chromosome positive chronic myelogenous leukemia by polymerase chain reaction

Blood ◽  
1989 ◽  
Vol 73 (8) ◽  
pp. 2165-2170
Author(s):  
MS Lee ◽  
A LeMaistre ◽  
HM Kantarjian ◽  
M Talpaz ◽  
EJ Freireich ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Chronic Myelogenous Leukemia ◽  
Philadelphia Chromosome ◽  
Rare Event ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Rt Pcr ◽  
Chain Reaction ◽  
Polymerase Chain ◽  
Minimal Residual

The Philadelphia (Ph′) chromosome in chronic myelogenous leukemia (CML) results in fusion of the bcr gene and c-abl oncogene, which transcribes into two types of chimeric bcr/abl mRNAs: the L-6 junction and the K-28 junction. By means of a highly sensitive assay, combination of reverse transcription and polymerase chain reaction (RT/PCR), we analyzed 38 blood samples obtained from 31 patients with Ph′-positive CML and two patients with Ph′-negative bcr rearranged CML. Among the 21 samples obtained in chronic phase, eight patients had the L-6 mRNA, 11 had the K-28 mRNA, and two had both the L-6 and K-28 mRNAs. Among the nine samples obtained in blast crisis, four contained the L-6 mRNA, two contained the K-28 mRNA, and three contained both the K-28 and L-6 mRNAs. This finding supports the concept of alternative splicing of bcr/abl mRNAs transcribed in Ph′-positive CML. However, it appears to be a rare event. Of the eight samples obtained from eight patients who had achieved complete cytogenetic remission and negativity for bcr region rearrangement for 6 months to 3 years after recombinant alpha interferon (r alpha-IFN) therapy, all of them showed evidence of minimal residual Ph′-positive clones as detected by the RT/PCR assay. This finding suggests that interferon therapy suppresses the proliferation of the Ph′-positive clones, but it does not completely eradicate the Ph′-positive stem cells.

scholarly journals Application of chromosome microdissection probes for elucidation of BCR- ABL fusion and variant Philadelphia chromosome translocations in chronic myelogenous leukemia

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3365-3371 ◽  
Author(s):  
J Zhang ◽  
P Meltzer ◽  
R Jenkins ◽  
XY Guan ◽  
J Trent
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Chromosome Rearrangement ◽  
Philadelphia Chromosome ◽  
Leukemic Cell ◽  
Myelogenous Leukemia ◽  
Chromosome Microdissection ◽  
Chromosome Translocations ◽  
Ph Chromosome

Abstract Fluorescence in situ hybridization (FISH) has become an increasingly important method for assessing chromosome rearrangement. The reciprocal translocation constituting the Philadelphia (Ph) chromosome [t(9;22)(q34;q11)] characterizes more than 90% of patients with chronic myelogenous leukemia (CML). However, in the remaining cases the Ph chromosome (genetically characterized by the fusion of the BCR-ABL genes) is thought to arise through complex translocations that are often not readily apparent using routine chromosome-banding analysis. For this reason we have developed unique band-specific probes for two- color FISH that detect unequivocally the Ph chromosome, and its derivatives. Results of the application of these probes are illustrated by analysis of 11 cases of CML (9 of which contain “variant” translocations). The probes were generated by chromosome microdissection and in vitro amplification of the bands involved in the Ph translocation, leading to an extremely fast and sensitive approach to identify this alteration in leukemic cell populations.

The Philadelphia-Chromosome Is Unmasked as the Secondary Genetic Change in Acute Myeloid Leukemia on Imatinib Treatment.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4557-4557
Author(s):  
Sze F. Yip ◽  
Thomas S.K. Wan ◽  
Herman S.Y. Liu ◽  
Michael L.G. Wong ◽  
Li C. Chan
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Imatinib Treatment ◽  
Rt Pcr ◽  
Monosomy 7 ◽  
Ph Chromosome ◽  
600Mg Daily ◽  
Acute Myeloid ◽  
Marrow Cells

Abstract The Philadelphia chromosome (Ph) is present in less than 3% of the acute myeloid leukemia (AML) and associated with poor prognosis. There are only few reports on the use of imatinib in Ph+ AML. We describe an adult female patient presenting with AML (Hb 3.6 g/dl, Wbc 137×109/L, Plt 295,000/uL and marrow blast 74%, with no basophilia or splenomegaly). Cytogenetic studies showed 45,XX,inv(3)(q21q26),-7,t(9;22)(q34;q11.2) [12] and RT-PCR showed p190BCR-ABL transcripts. The leukemia failed to respond to 2 cycles of daunorubicin and ara-C and imatinib 600mg daily was then started. Fluorescence in-situ hybridization (FISH) analysis of 300 marrow cells using dual fusion BCR-ABL translocation probes (D-FISH, Vysis, Downers Grove, IL, USA) showed that before imatinib, 78% of the cells were positive for BCR-ABL (at diagnosis, it was 83%), which after 6 weeks of imatinib treatment, became BCR-ABL negative (sensitivity 0.3%). However, marrow biopsy still showed 15% blasts. Repeated cytogenetics showed poor growth, but one metaphase showed 45,XX,inv(3)(q21q26),-7. With FISH, 39% of the marrow cells, including neutrophils, were positive for monosomy 7. At 4 months of imatinib, when the marrow blasts count increased to 40%, BCR-ABL remained negative by FISH, whereas monosomy 7 positive cells had risen to 82%. However, by nested RT-PCR with sets of BIOMED primers (sensitivity of 10−5), the p190BCR-ABL transcript was still present, suggesting persistence of a small and quiescent population of BCR-ABL positive leukemic stem cells. In summary, our case study demonstrates the need for careful cytogenetic and molecular analysis in cases of acute leukaemia with Ph chromosome to exclude the possibility of Ph chromosome being a secondary event, in which case durable leukemia remission will be unlikely if treatment is by BCR-ABL inhibition alone.

scholarly journals Application of chromosome microdissection probes for elucidation of BCR- ABL fusion and variant Philadelphia chromosome translocations in chronic myelogenous leukemia

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3365-3371
Author(s):  
J Zhang ◽  
P Meltzer ◽  
R Jenkins ◽  
XY Guan ◽  
J Trent
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Chromosome Rearrangement ◽  
Philadelphia Chromosome ◽  
Leukemic Cell ◽  
Myelogenous Leukemia ◽  
Chromosome Microdissection ◽  
Chromosome Translocations ◽  
Ph Chromosome

Fluorescence in situ hybridization (FISH) has become an increasingly important method for assessing chromosome rearrangement. The reciprocal translocation constituting the Philadelphia (Ph) chromosome [t(9;22)(q34;q11)] characterizes more than 90% of patients with chronic myelogenous leukemia (CML). However, in the remaining cases the Ph chromosome (genetically characterized by the fusion of the BCR-ABL genes) is thought to arise through complex translocations that are often not readily apparent using routine chromosome-banding analysis. For this reason we have developed unique band-specific probes for two- color FISH that detect unequivocally the Ph chromosome, and its derivatives. Results of the application of these probes are illustrated by analysis of 11 cases of CML (9 of which contain “variant” translocations). The probes were generated by chromosome microdissection and in vitro amplification of the bands involved in the Ph translocation, leading to an extremely fast and sensitive approach to identify this alteration in leukemic cell populations.

scholarly journals Group-specific human granulocyte antigens on a chronic myelogenous leukemia cell line with a Philadelphia chromosome marker

Blood ◽  
1977 ◽  
Vol 49 (5) ◽  
pp. 715-718 ◽  
Author(s):  
SI Drew ◽  
PI Terasaki ◽  
RJ Billing ◽  
OJ Bergh ◽  
J Minowada ◽  
...  
Keyword(s):  
Cell Line ◽  
Chronic Myelogenous Leukemia ◽  
B Lymphocyte ◽  
Philadelphia Chromosome ◽  
Leukemia Cell ◽  
Myelogenous Leukemia ◽  
Leukemia Cell Line ◽  
Chromosomal Marker ◽  
Chronic Myelogenous Leukemia Cell ◽  
Chromosome Marker

Group-specific human granulocyte antigens are serologically detectable with granulocytotoxic-positive human alloantisera on a cell line, K562, of chronic myelogenous leukemia origin which bears a Philadelphia chromosomal marker. The same cell line lacks serologically detectable HLA, B2 microglobulin, and B-lymphocyte antigens. Granulocyte antigens are important cell markers for cell lines of suspected myeloid lineage.

scholarly journals Philadelphia chromosome-negative chronic myelogenous leukemia without breakpoint cluster region rearrangement: a chronic myeloid leukemia with a distinct clinical course

Blood ◽  
1990 ◽  
Vol 75 (2) ◽  
pp. 445-452 ◽  
Author(s):  
R Kurzrock ◽  
HM Kantarjian ◽  
M Shtalrid ◽  
JU Gutterman ◽  
M Talpaz
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Chronic Myelogenous Leukemia ◽  
Myeloid Leukemia ◽  
Clinical Course ◽  
Bone Marrow Failure ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Cell Counts

Abstract The hallmarks of chronic myelogenous leukemia (CML) include the Philadelphia chromosome (Ph) translocation [t (9;22)(q34;q11)] and consistent molecular genetic aberrations: a break within a restricted 5.8 kb DNA segment, bcr, on chromosome 22q11; transposition of the c- abl protooncogene from chromosome 9q34 to 22q11; and formation of a hybrid bar-abl gene encoding an abnormal 210 Kd bcr-abl protein with augmented tyrosine kinase enzymatic activity. These molecular phenomena may occur even in the absence of cytogenetic evidence of the Ph translocation. They are highly specific and sensitive markers for CML, and are presumed to play a significant role in the pathogenesis of this malignancy. Surprisingly, we have encountered 11 patients who lacked the Ph translocation, bcr rearrangement, and (in the four patients with available mRNA) a bcr-abl message, and yet had a disease phenotype at diagnosis that was a morphologic facsimile of classic chronic phase CML. These patients presented with high white blood cell counts, neutrophilia, occasional basophilia, splenomegaly, and a hypercellular bone marrow with granulocytic hyperplasia and a left shift in myeloid maturation. Despite the striking resemblance between the early stages of bcr-negative and bcr-positive CML, disease progression manifests distinctly in these two disorders. In contrast to the blastic transformation that inevitably complicates bcr-positive CML, the natural history of our 11 Ph-negative, bcr-negative CML patients was characterized by increasing leukemia burden with leukocytosis, pronounced organomegaly, extramedullary infiltrates, and eventual bone marrow failure (anemia and thrombocytopenia) without marked increases in blast cells. Our current observations suggest that a chronic myeloid leukemia process can develop without associated changes in the bcr or c- abl genes. Although the initial phase of this disease is indistinguishable from CML, the presence or absence of molecular markers may aid in the prediction of the clinical course of Ph-negative CML.

scholarly journals Interleukin (IL)-1 Beta and IL-6 Activated Acute and Chronic Myelogenous Leukemia-Derived Myofibroblasts to Express Leukemia-Specific Transcripts

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5094-5094
Author(s):  
Takuji Matsuo ◽  
Haruko Tashiro ◽  
Ritsu Sumiyoshi ◽  
Tadashi Yamamoto ◽  
Kensuke Matsumoto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myelogenous Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Specific Antigen ◽  
Myelogenous Leukemia ◽  
Pcr Analysis ◽  
Fish Analysis ◽  
Rt Pcr ◽  
Single Colony

Abstract Background and Aims: We previously reported that interleukin 1-beta (IL-1-b) stimulated bone-marrow stromal myofibroblasts from normal individuals to express CD34. And, when myofibroblasts were cultured with IL-1-b and IL-6, GATA-2 and CD45 expressed. We report here that bone marrow-derived myofibroblasts from acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) patients were also activated to express leukemia-specific molecules when IL-1-b and IL-6 were added to the cultures. Materials and Methods: Bone marrow samples were collected from informed 7 AML patients (2 cases of M2 with t(8;21), 3 of M0, M2, and M7 positive for FLT-ITD mutation, 2 of Philadelphia-positive bi-phenotypic acute leukemia (Ph-AL)), and 3 CML ones, whose mononuclear cells were separated, and were cultured, split, and re-cultured for one month to eliminate non-adherent cells, vascular cells, and monocytes/macrophages to prepare myofibroblasts. The obtained cells were further cultured for one more month to obtain myofibroblasts with stably growth, and then leukemia-specific molecules (FLT3-ITD, BCR-ABL1 fusion (major and minor), RUNX1-RUNX1T1 fusion) were analyzed at DNA and RNA levels. Cells were further cultured with IL-1-b and IL-6 for two weeks, and morphological changes and expressions of specific molecules were observed. Results: When bone marrow-derived myofibroblast obtained from myeloid leukemia patients were analyzed, leukemia-specific molecules were detected at DNA levels (FISH analysis detected 0.5-5% BCR-ABL1 fusion in CML- and Ph-AL-derived myofibroblast-cultures, 1-2% RUNX1- RUNX1T1 in AML with t(8;21)-cultures, and positive FLT3-ITD mutation at genomic PCR in AML-cultures); however, RT-PCR analyses revealed that leukemia-specific transcripts were not detected in all cells. When myofibroblasts were cultured with IL-1-b and IL-6, leukemia-specific transcripts were detected with RT-PCR analysis in all cases. Also, CD45, and GATA-2 expressed in these cultures. Discussion: We reported previously that a few populations of bone marrow-derived myofibroblasts obtained from AML and CML patients expressed leukemia-specific transcripts and proteins when cultured as a separated single colony; however, when myofibroblasts were cultured not as a fractionated single colony but a whole stromal cells for a long term, expression of leukemia-specific molecules weakened and no longer confirmed. Myofibroblasts with leukemic character seem to stop their proliferation and keep dormant. One interesting point is that normal stromal myofibroblasts derived from myeloid leukemia patients can inhibit the growth of myofibroblasts that have leukemic characters. Some mechanisms may work on this observation. Also, an important issue is that myofibroblasts reportedly have an ability of antigen presentation. If some myofibroblasts can express leukemia-specific molecules as well as HLA when cultured with IL-1-b and IL-6, they can act as a leukemia-specific antigen-presenting cell. We now attempt to research this theme to develop a new cell-mediated vaccine for myeloid leukemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals Human chronic myelogenous leukemia cell-line with positive Philadelphia chromosome

Blood ◽  
1975 ◽  
Vol 45 (3) ◽  
pp. 321-334 ◽  
Author(s):  
CB Lozzio ◽  
BB Lozzio
Keyword(s):  
Cell Line ◽  
Chronic Myelogenous Leukemia ◽  
Culture Media ◽  
Specific Antigen ◽  
Philadelphia Chromosome ◽  
Experimental Studies ◽  
Leukemia Cell ◽  
Myelogenous Leukemia ◽  
Chromosome 17 ◽  
Leukemia Cell Line

A cell-line derived from a patient with chronic myelogenous leukemia (CML) is described. The new cell-line, which has over 175 serial passanges in a 3 1/2-yr period, has the following characteristics: (1) CML cells started to proliferate actively since they were first incubated in culture media. A threefold increase in the total number of cells was observed during the first seven passages; the cell population increased by a factor of 10 to 20 every 7 days from passage 8 through 85; from 20 to 40 times from passage 86 through 150, and more than 40 times after 150 passages. (2) The majority of the nononucleated cells are undifferentiated blasts. (3) The karyotype of all the cells examined show the Philadelphia (Ph1) chromosome and a long acrocentric marker plus aneuploidy. The Giemsa-banding studies identified the Ph1 chromosome as a terminal deletion of the long arm of chromosome 22:del(22)(q12) and the long acrocentric marker as an unbalanced reciprocal translocation of one chromosome 17 and the long arm of one chromosome 15. (4) The CML cells do not produce immunoglobulins, are free of mycoplasma, Epstein-Barr virus, and herpes-like virus particles. (5) CML cells have no alkaline phosphatase and myeloperoxidase activities and did not engulf inert particles. (6) Cultured CML cells provide a constant source of a specific antigen. This CML cell-line represents a unique source of CML cells with meaningful indicators of malignancy for clinical and experimental studies.

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