Occurrence Of Chronic Myeloid Leukemia Research Articles

CircCRKL, a circRNA derived from CRKL, regulates BCR-ABL via sponging miR-877-5p to promote chronic myeloid leukemia cell proliferation

BackgroundThe BCR-ABL fusion protein is the key factor that results in the occurrence of chronic myeloid leukemia (CML). Imatinib (IM) is a targeted inhibitor of BCR-ABL to achieve complete remission. However, remission failure occurs due to acquired resistance caused by secondary BCR-ABL mutations, underlining the need for novel BCR-ABL-targeting strategies. Circular RNAs (circRNAs) derived from tumor-related genes have been revealed as possible therapeutic targets for relevant cancers in recent investigations. In CML, the roles of this kind of circRNA are yet obscure.MethodsFirstly, RT-qPCR was used for determining circCRKL expression level in cell lines and clinical samples, RNase R and Actinomycin D were employed to verify the stability of circCRKL. Then shRNAs were designed to specifically knockdown circCRKL. The function of circCRKL in vitro was investigated using CCK-8, colony formation assay, and flow cytometry, while a CML mouse model was constructed to explore the function in vivo. Finally, a dual-luciferase reporter assay, RNA pull-down, RNA immunoprecipitation, and rescue experiments were conducted to investigate the mechanism of circCRKL functioning.ResultsHere, we determined circCRKL, which derives from CML-relevant gene CRKL, is over-expressed in BCR-ABL+ cells. Then we noticed knocking down circCRKL using shRNA lentivirus dampens the proliferation of BCR-ABL+ cells both in vitro and in vivo, and augments susceptibility of resistant cells to IM. Intriguingly, we observed that circCRKL has a considerable impact on the expression level of BCR-ABL. Mechanistically, circCRKL could behave like a decoy for miR-877-5p to enhance the BCR-ABL level, allowing BCR-ABL+ cells to maintain viability.ConclusionsOverall, the current study uncovers that circCRKL is specifically expressed and regulates BCR-ABL expression level via decoying miR-877-5p in BCR-ABL+ cells, highlighting that targeting circCRKL along with imatinib treatment could be utilized as a potential therapeutic strategy for CML patients.

Research on the Mechanism of SIRT1/AMPK Inducing Resistance to Imatinib in K562 Cells By Inhibiting Srebp to Promote Lipid Metabolism

Background Leukemia stem cells (LSC) have the characteristics of independent of BCR-ABL kinase activity and metabolic reprogramming to support self-renewal. They are the root cause of the occurrence of chronic myeloid leukemia (CML), mediating TKI resistance and leading to clonal evolution. LSC self-renewal depends on the activity of SIRT1, the enhanced of SIRT1 induces LSC mitochondrial metabolic reprogramming. Studies have shown that SIRT1 and abnormally activated lipid metabolism are important reasons for inducing CML resistance to imatinib.Objective Study the mechanism of SIRT1 regulating lipid metabolism and intervention strategies under imatinib therapy.Method Liquid chromatography coupled with mass spectrometry (LC-MS) were used to analysis the lipid metabolism in imatinib-resistant CML cell line K562-R under low-glucose conditions. RT-qPCR and Western blot were used to detect the key enzymes related to lipid metabolism, and the SIRT1 inhibitor TV-6 was given to study the regulation mechanism of SIRT1 on lipid metabolism.Result Firstly, we found that the glycolysis/gluconeogenesis pathway and fatty acid metabolism were abnormal in K562-R cells by metabolomics, compared with normal culture conditions, the expression of SIRT1 and AMPK were significantly increased, the expression of fatty acid synthesis-related genes (SREBP, FASN, ACC, SCD1) was significantly reduced, and the fatty acid β oxidation rate-limiting enzyme CPT-1 is significantly increased inK562-R cells under low-glucose conditions. Therefore, in the low-glucose environment, the expression of the above genes was reversed after the application of the SIRT1 inhibitor TV-6.Conclusion K562-R imatinib-resistant cells can down-regulate the expression of SREBP through up-regulated SIRT1/AMPK pathway under low-glucose conditions, thereby inhibiting the expression of transcription factors involved in lipogenesis, reducing fatty acid synthesis, and providing the imatinib-resistant cells with the energy which required for proliferation.Keyword Chronic myeloid leukemia; Metabolomics; Lipid metabolism; SIRT1/AMPK DisclosuresNo relevant conflicts of interest to declare.

Anesthesia consideration for cesarean section in chronic myeloid leukemia diagnosed during pregnancy: An interesting case report and brief review of literature

Chronic myeloid leukemia (CML) is a myeloproliferative disorder with clonal expansion of transformed primitive hematopoietic progenitor cells without loss of their capacity to differentiate. Annual incidence of CML in females ranges from 0.6 to 1.6 per 100,000 populations. In developing countries like India where onset of hematological malignancy occurs in early age, thereby increases chances of concomitant occurrence of CML and pregnancy together. Although the incidence is rare, anesthesia management of pregnant female presenting more so for an emergency cesarean section (C/S) is challenging because of the physiological changes during pregnancy, presence of anemia, coagulopathy, immunosuppressant drugs, leukocytosis, and rarely blast cells in circulation. We report the successful management of a 19-year-old primigravida, recently diagnosed with CML, planned for emergency C/S under general anesthesia in view of meconium-stained liquor with fetal distress.

Multiplexed Quantitative MALDI MS Approach for Assessing Activity and Inhibition of Protein Kinases Based on Postenrichment Dephosphorylation of Phosphopeptides by Metal–Organic Framework-Templated Porous CeO2

Protein kinase is regarded as a potential target for anticancer therapeutics due to its relation to many diseases, in which more than one kinase participates in the cell signaling cascades. We herein demonstrate a multiplexed quantitative matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) approach to simultaneously assess the activity and inhibition of multiple protein kinases. In this design, substrate peptides phosphorylated by kinases of interest are specifically harvested by metal-organic framework (MOF)-templated porous CeO2 and consequently transformed to the dephosphorylated forms due to the phosphatase-like activity of CeO2, resulting in a unique quantitative MS signal with an enhanced intensity. Based on the peak area ratios of dephosphorylated variants of the phosphorylated product to respective deuterated internal standard, the activity and inhibition of each kinase can be independently profiled. In addition to the accurate characterization of protein kinase A (PKA) activity and inhibition induced by H-89, the multiplexing capability of the MS-based method allowed quantitative evaluation of the activity of Abl and Src, the two tightly associated kinases in the occurrence of chronic myeloid leukemia (CML) in a multiplexed format, exhibiting excellent orthogonality for the dual signal readout channels. Moreover, the inactivation of both Abl and Src by the inhibitor imatinib, dasatinib, and ponatinib was simultaneously traced, giving a whole picture of the competition behavior between the kinases for binding therapeutic molecules. This approach holds great promise in global investigation of kinase signal pathways and high-throughput screening of effective protein kinase inhibitors.

Variation of LNK Gene in Chronic Myeloid Leukemia

To compare the mutation and single nucleotide polymorphism (SNP) of LNK gene between chronic myeloid leukemia(CML) and control groups, and to explore the relationship between LNK gene variation and the occurrence of CML. A total of 36 patients with CML were selected, 46 healthy persons were used as normal controls. DNA was extracted from bone marrow and peripheral blood, BCR/ABL1 fusion gene was detected by Q-PCR. The whole exon of LNK gene was amplified by PCR. The amplified sequences included the Rs3184504 (C/T) and Rs78894077 (A/C/G/T) affecting the expression of amino acids in LNK gene, and the Rs7973120 (A/T) unaffecting the expression of the amino acids. The mutations and SNP of LNK gene were analyzed by DNA sequencing. Thirty-six cases of CML had BCR/ABL1 mutation, while no mutation was found in the control group. One case of CML had LNK heterozygous mutation (A300V), and the mutation rate was 2.8%, no mutation was seen in normal control group. Rs3184504: C/T allele frequency was 50%/50% in the control group, 94.4%/5.6% in the CML group, and the C allele in CML group was significantly higher than that in the control group; CC genotype accounted for 94.4% (P<0.01). Rs78894077: C/T allele in the control group was 9.8%/90.2%, in CML group was 16.7%/83.3%, the difference was not statistically significant(P>0.05); but CC genotype in CML group was very statistically significant higher than that in control group(P<0.01). Rs7973120: A/T allele frequency was 10.9%/89.1% in the control group, 25%/75% in the CML group, the LNK A allele in CML group was very significantly higher than that in control group (P<0.01). CML patients have been confirmed to have LNK mutation; the SNPs of LNK are related with the development of CML, and the most CML patients carry the LNK Rs3184504 C allele and the Rs7973120 A allele.

Synchronous Occurrence of Chronic Myeloid Leukemia and Mantle Cell Lymphoma

Chronic myeloid leukemia (CML) and mantle cell lymphoma (MCL) are hematologic malignancies that originate from different oligopotent progenitor stem cells, namely, common myeloid and lymphoid progenitor cells, respectively. Although blastic transformation of CML can occur in the lymphoid lineage and CML has been related to non-Hodgkin lymphoma on transformation, to our knowledge, de novo and synchronous occurrence of CML and MCL has not been reported. Herein, we report the first case of synchronous CML and MCL in an otherwise healthy 38-year-old man. Potential etiologies and pathological relationships between the two malignancies are explored, including the possibility that the downstream effects of BCR-ABL may link it to an overexpression of cyclin D1, which is inherent to the etiology of MCL.

An Uneventful Pregnancy and Delivery in a Patient with Chronic Myeloid Leukemia

ABSTRACT The concomitant occurrence of chronic myeloid leukemia and pregnancy is estimated to be one in 75000-100000 pregnancies annually. We present a case of 28 years old lady with 36 weeks of gestation diagnosed as chronic myeloid leukemia in chronic phase. Her pregnancy and delivery was uneventful. She breast fed the baby for 3 weeks before initiating treatment. Close vigilance and relevant investigations are of paramount importance in recognizing this extremely rare disease during pregnancy. How to cite this article Prathima S, Prasad CSBR, Kumar U, Narayanswamy M. An Uneventful Pregnancy and Delivery in a Patient with Chronic Myeloid Leukemia. J South Asian Feder Menopause Soc 2014;2(1):33-34.

Chronic myeloid leukemia as a secondary malignancy after diffuse large B-cell lymphoma

Chronic myeloid leukemia as a secondary malignancy after diffuse large B-cell lymphoma

Simultaneous occurrence of chronic myeloid leukemia and chronic lymphocytic leukemia: Report of an unusual case

The coexistence of chronic myeloid leukaemia(CML) and chronic lymphocytic leukemia(CLL) has been reported occasionally in literature, with only seven cases of simultaneous occurrence of these two diseases. We present here a case of 57 yr male patient where a complete blood count and differential done using volume conductivity scatter (VCS) technology suggested a diagnosis of CML with CLL. It was further confirmed by immunophneotyping and cytogenetic analysis. The patient was started on tyrosine kinase inhibitor, 400 mg once daily. Four months after the treatment, patient is doing fine with a count of 22 × 10 9 /L and 64% lymphocytes.

Coexistence of chronic myeloid leukemia and pulmonary plasmacytoma mimicking primary lung cancer

A 61-year-old man was diagnosed with the simultaneous occurrence of chronic myeloid leukemia (CML) and infiltrative intrathoracic plasmacytoma, radiologically mimicking bronchogenic carcinoma. Following the administration of imatinib mesylate (IM; 400mg/day), both hematologic and partial cytogenetic remission of CML were achieved. However, the pulmonary plasmacytoma was persistently aggravated. High-dose dexamethasone was added to the IM therapy because the patient refused radiotherapy to control the aggravated pulmonary plasmacytoma. Finally, he died due to pneumonia and multi-organ failure during concurrent administration of IM and high-dose dexamethasone.

Concomitant or Sequential Chronic Lymphocytic Leukemia (CLL) and Chronic Myeloid Leukemia (CML): A Molecular and Clinical Survey

Brief Abstract A 75-year-old man presented with B-CLL followed by a CML. We retrospectively analyzed the frozen BM and PB lymphocytes that evidenced 2 distinct clonal proliferations: one is a B CD5+/CD19+ lymphocyte population, without BCR-ABL fusion; the other is the CD19+ mononuclear cell population expressing traces of BCR-ABL, 3 years before the occurrence of CML. We suggest that (1) the emergence of the Ph+ clone after the treatment of CLL is probably related to RFC-induced immunosuppression, and (2) the long DFS of CLL might be due to the current TK inhibitor treatment Full Abstract Introduction The coexistence of B-cell chronic lymphocytic leukemia (B-CLL) and chronic myeloid leukemia (CML) is a rare event. This coexistence has led to speculation of the clonal origin of these neoplasms. In some cases, 2 independent clones were demonstrated. Patients and Methods A 75-year-old man presented with splenomegaly and enlarged lymph nodes. Immunophenotype (kappa, CD19+, CD5+, CD23+) was compatible with B-CLL. Bone marrow examination showed infiltration by small lymphocytes next to a myeloid and megakaryocytic hyperplasia. Cytogenetic analysis of the marrow showed 46XY, del(16q). Philadelphia chromosome (Ph) was negative. The patient was diagnosed with B-CLL and treated by 6 RFC (rituximab/fludarabine/cyclophosphamide). He reached a molecular remission (MCR), but 3 years after the treatment for CLL, he developed hyperleukocytosis (26000/μL), mainly myeloid cells. Bone marrow smear demonstrated a myeloid hyperplasia with predominance of immature progenitors. The Ph was clearly evidenced, and CML was confirmed. The patient thus received thus imatinib 400 mg/day orally with hematologic but only partial molecular remission at 18 months. A Y25.3H mutation was detected, and the patient was switched to dasatinib with a successful evolution. The CLL remained in MCR during this 5-year period. Results To know whether CML is a secondary event induced by RFC treatment or the emergence of a latent CML clone, we analyzed retrospectively the frozen BM and PBL lymphocytes. The results were consistent with the view that there are 2 distinct clonal proliferations: one is a clonal B CD5+/CD19+ lymphocyte population, without BCR-ABL fusion; the other is the CD19+ mononuclear cell population expressing traces of BCR-ABL, 3 years before the occurrence of CML. Conclusion Our data provide evidence for a separate clonal origin for each disorder, raising the hypothesis that (1) the emergence of the Ph+ clone after the treatment of CLL is probably related to RFC-induced immunosuppression, and (2) the long disease-free survival of CLL might be due to the current tyrosine kinase inhibitor treatment.

Two successful pregnancies in a woman with chronic myeloid leukemia exposed to nilotinib during the first trimester of her second pregnancy: case study

The occurrence of chronic myeloid leukemia in pregnancy is rare and its management poses a clinical challenge for physicians treating these patients. We report a 30-year-old woman with chronic myeloid leukemia who became pregnant twice successfully. Philadelphia-positive CML in its chronic phase was diagnosed at 16 weeks of her first gestation. At that time, she received no treatment throughout her pregnancy. At 38 weeks of gestation, a normal infant was delivered by cesarean section. At six weeks postpartum, the patient underwent imatinib mesylate therapy but she could not tolerate the treatment. The treatment was then changed to nilotinib at 400 mg orally b.i.d. Two years later, she became pregnant again while she was on nilotinib 200 mg b.i.d. The unplanned pregnancy was identified during her 7.4 weeks of gestation. Because the patient elected to continue her pregnancy, nilotinib was stopped immediately, and no further treatment was given until delivery. Neither obstetrical complications nor structural malformations in neonates in both pregnancies were observed. Both babies' growth and development have been normal. Although this experience is limited to a single patient, the success of this patient demonstrates that the management of chronic myeloid leukemia in pregnant women may be individualized based on the relative risks and benefits of the patient and fetus.

Presence of Bcr-Abl Positive Cells in Peripheral Blood Leukocytes of Immunosuppressed Solid Organ Transplant (SOT) Recipients

In chronic myeloid leukemia (CML) the p210 BCR-ABL protein, generated by a t(9;22)(q34;q11) translocation, is the underlying mechanism of leukemogenesis. Although the presence of p210 BCR-ABL is normally restricted to CML patients (pts), previous reports demonstrated low levels of bcr-abl transcripts in healthy individuals that may be controlled by an intact immune system (Bose et al. Blood 92:3362, 1998). Interestingly, several articles reported cases of CML occurring in pts after SOT (Pelloso et al. Leukemia Res 29:353, 2005). Therefore, immunosuppressed SOT recipients should represent an optimal population to investigate the frequency of bcr-abl transcripts in non-leukemic individuals in order to address a potential impact of immunosuppression on the presence of bcr-abl transcripts. This possibility was investigated by studying peripheral blood leukocytes for the presence of bcr-abl transcripts in a total of 201 individuals of whom 100 were SOT recipients (n=50 kidney, n=46 liver, n=3 heart, n=1 heart-lung) and 101 were control individuals (n=87 patients with renal failure, n=14 healthy individuals). The male to female ratio in the study group was 54:46 (median age: 55.38 years, range: 22–83) and matched the control group (median age: 59.8 years, range: 32–96). Included in the study group were 13 pts with post transplant malignancies who were previously treated with standard chemotherapeutic regimens. Immune suppressive drugs given to all SOT recipients included steroids (90%), cyclosporine A (69%), azathioprine (22%), tacrolimus (69%), sirolimus (44%), mycophenolic acid (63%) and others (37%). For the detection of the bcr-abl transcript we used a nested reverse transcriptase-polymerase chain reaction (RT-PCR) assay that is routinely used in our institution. All samples were tested at least twice. In 5/100 immunosuppressed pts at least 1 of 2 RT-PCR products was bcr-abl positive in the second round amplification. This rate significantly exceeded the control group that was completely bcr-abl negative (0/101 p = 0.0242). Of the 5 bcr-abl positive pts, 3 were liver transplant and 2 were kidney transplant recipients. The latency in this group (interval between transplantation and bcr-abl PCR) was at 58.4 months (range: 24-135 months) and shorter when compared to the latency in the remaining study group (104.8 months; range 1 – 369). Additionally, all samples were tested for both the pml-rara and aml1-eto transcripts that are detectable in subsets of pts with acute myeloid leukaemia but none of the samples tested positive for these transcripts. Our findings are extended by three case reports of SOT recipients (2 kidney, 1 liver) who developed CML in a total of 2088 transplantations in our centre in 9 years. In these three pts (2 males, 1 female), CML occurred at 84.3 months (range: 32–183) following SOT. In summary our data show: 1. The presence of bcr-abl transcripts in immunosuppressed non-leukemic SOT pts and the absence of bcr-abl transcripts in healthy normals when tested with routine PCR protocols. 2. The absence of pml-rara and aml1-eto transcripts in both the study and control group. And 3. the occurrence of CML in three patients following SOT suggesting a higher frequency of CML in this population.

Concurrent Mediastinal B Cell Lymphoma and Chronic Myeloid Leukemia with an Unusually Favorable Response to Chemotherapy

A 67-year-old Chinese woman presented with mediastinal B cell lymphoma in 1992 with incidental leukocytosis. Bone marrow and peripheral blood findings confirmed the diagnosis of chronic myeloid leukemia (CML). After combination chemotherapy and radiotherapy for lymphoma, her peripheral blood counts remained normal, and she refused further treatment for nearly six years. Frank hematologic relapse occurred in 1998 and low dose hydroxyurea was used, which was stopped after six months owing to cytopenia. She remained well without treatment at 12-year follow up. Retrospective Southern blot analysis confirmed BCR gene rearrangement in marrow in 1992 and 1998, but not in the lymphoma or the latest peripheral blood. Fluorescence in-situ hybridzation analysis showed no Philadelphia chromosome positive (Ph + ) cells in the peripheral blood at last (FISH) follow-up, but BCR/ABL remained detectable. The relevance of the concomitant occurrence of CML and lymphoma and the unusually favorable response of CML to chemotherapy to the pathogenesis of CML is discussed.

Chronic Myeloid Leukemia in Waldenström's Macroglobulinemia

Eighteen months after the occurrence of Waldenström's macroglobulinemia, Philadelphia (Ph1) chromosome-positive chronic myeloid leukemia developed in a 69-year-old woman. The coexistence of the two disorders was characterized by an initial reduction of paraproteinemia at the time that leukemia occurred, a long-lasting remission of the two disorders, and a final parallel increase of paraproteins and WBCs. Since leukemia occurred 15 months after the interruption of melphalan therapy, the potential mutagenic role of chemotherapy was considered irrelevant. Therefore, Waldenström's macroglobulinemia might favor the occurrence of chronic myeloid leukemia.