Focal lymphoblastic transformation of chronic myelogenous leukemia develops into erythroid leukemia:A case report

BACKGROUND We present a case of focal lymphoblastic transformation to erythroid leukemia following acute myeloblastic transformation in a patient with chronic myelogenous leukemia(CML)and discuss its mechanism of occurrence and development.CASE SUMMARY The presence of the Philadelphia(Ph)chromosome was identified through karyotype analysis,while the BCR-ABL fusion gene was detected using quantitative real-time polymerase chain reaction of the peripheral blood sample.Fluorescence in situ hybridization was used to detect the expression of the BCRABL gene in the lymphoma.Antigen expression and gene mutations in the primitive cells were detected by flow cytometry.The analysis confirmed the presence of CML along with focal lymphoblastic transformation to erythroid leukemia.Additionally,the patient was found to have secondary erythroid leukemia,along with multiple new gene mutations and abnormalities in complex karyotypes of chromosomes.CONCLUSION Our findings suggest a possible molecular basis for the focal lymphoblastic transformation secondary to myeloblastic transformation in patients with CML.

HIM_(1) AND HIM4, TWO MONOCLONAL ANTIBODIES POTENTIALLY USEFUL FOR AUTOLOGOUS BONE MARROW TRANSPLANTATION IN CHRONIC MYELOGENOUS LEUKEMIA

We developed two complement-fixing MoAbsHIMand HIM(murine)that were specifically reac-tive with chronic myelogenous leukemia (CML) cells.They were capable of fixing human or rabbit com-plement and suitable for CML cells purging of re-mission marrow from CML patients.HIMreactedwith majority leukemic cells form 7 out of 10 CMLpatients by complement-mediated cytotoxicity(C’MC)assay(positive cells 80%—90%),HIMreacted withmajority CML cells from 4 out of 5 CML by C’MCassay(positive cells 80%—90%).Treatment withHIMor HIMand human C’was capable of lysing97% of K562,U937,HL-60 and CML cells in a 20fold excess of unrelated cells by indirect FITC+EBstain.Using limited dilution culture,incubation withHIMand C’produced 1.5 logs inhibition of growthin K562 cells,and 1.9 logs in U937 cells,and withHIMand C’produced 2.9 logs inhibition in HL-60cells and 3.0 logs in U937 cells.Both MoAbs cocktailwas shown 1.8 logs in K562 cells and 3.2 logs in U937cells.They were no suppression on the growth o

Redistribution of Platelet Membrane Glycoprotein IV and Release of Intracellular α-granule Thrombospondin in Patients with Chronic Myelogenous Leukemia

The redistribution of platelet membrane glycoprotein IV (GPIV) and the release of intracellular Q-granule thrombospondin (TSP) were examined and the inhibition of 5-thromboglobulin (&TG) and platelet factor 4 (PF4) in patients with chronic myelogenous leukemia (CML) was observed and quantitation of β-TG and PF4 in sera was conducted. GPIV in inactive platelet from CML was 36080±17010 molecules/platelet as compared with 13190±4810 from the controls (P<0,01), No abnormality was found in the distribution of platelet membrane GPIb and GPIIb/III.(P>0. 05). The GPIV redistribution on active platelet membrane induced thrombin (1U/ml) from CML and healthy donors was 44320132310 and 228001 12700 molecules/platelet respectively (P<0. 01 ). The difference in the release of intracellular Q-granule TSP between CML and the control group was not found (P>0.05). There was no direct correlation between GPIV expression and TSP binding after platelet activation. The high leveIs of β-TG and PF4 in sera inhibited release of intracellular a-granule TSP in vitro. These results indicate that the abnormality of platelet membrane GPIV is a common marker in CML, therefore the specific increase of platelet GPIV in patients with CML may be a useful tool for the diagnosis and monitoring of the platelet dysfunction. The release of interna1 TSP pools is hindered by either β-TG or PF4 in sera.

Research on Marketing Strategies of Product D—a Chronic Myelogenous Leukemia Drug for Pharmaceutical Company A

Objective To put forward some suggestions on the marketing strategies for chronic myelogenous leukemia in a pharmaceutical enterprise.Methods Based on the development status of the pharmaceutical industry and the SWOT analysis of a company’s product,the marketing strategies were formulated to provide theoretical basis for pharmaceutical enterprise to adapt to the new medical reform.Results and Conclusion Nowadays,due to fierce competition,in order to expand the new market,enterprises should implement the strategies of new products,centralized management and professional training.Meanwhile,the effective marketing strategies should be formulated and strictly carried out according to the conditions of the pharmaceutical company.

Myeloid sarcoma presenting as a colon polyp and harbinger of chronic myelogenous leukemia

Myeloid sarcoma, also known as granulocytic sarcoma or chloroma is an unusual accumulation of malignant myeloid precursor cells in an extramedullary site, which disrupts the normal architecture of the involved tissue. It is known to occur more commonly in patients with acute myelogenous leukemia and less commonly in those with myelodysplastic syndrome and myeloproliferative neoplasm, such as chronic myelogenous leukemia. The most common sites of involvement include bone, skin and lymph nodes. However, rare cases have been reported in the gastrointestinal tract, genitourinary tract, or breast. Most commonly, a neoplastic extramedullary proliferation of myeloid precursors in a patient would have systemic involvement of a myeloid neoplasm, including in the bone marrow and peripheral blood. Infrequently, extramedullary disease may be the only site of involvement. It may also occur as a localized antecedent to more generalized disease or as a site of recurrence. Herein, we present the first case in the English literature of a patient presenting with an isolated site of myeloid sarcoma arising in the form of a colonic polyp which, after subsequent bone marrow biopsy, was found to be a harbinger of chronic myelogenous leukemia.

Suspected coexistence of perianal necrotizing sweet syndrome in chronic myelomonocytic leukemia:A case report

BACKGROUND Chronic myelomonocytic leukemia(CMML)complicated with Sweet syndrome(SS)is a rare hematological neoplasm.However,cases of concomitant development of perianal necrotizing SS(NSS)have not been reported.CASE SUMMARY We report a case of a 49-year-old male patient who underwent sequential procedures for hemorrhoids and perianal abscess.He developed postoperative incision infection and was referred to the department where the authors work.Initially,perianal necrotizing fasciitis secondary to incision infection after perianal abscess surgery was suspected.Despite receiving antibiotic therapy and undergoing surgical debridement,deeper necrotic areas formed in the patient’s perianal wounds,accompanied by persistent high fever.Blood and fungal cultures yielded negative results.The final diagnosis was corrected to be CMML with suspected concomitant perianal NSS.CONCLUSION CMML with perianal NSS is a rare condition,often misdiagnosed as perianal abscess or perianal necrotizing fasciitis.Conventional antibiotic therapy and surgical debridement are ineffective in managing this condition.

Network pharmacology to decipher the mechanism of Danggui Longhui Wan against chronic myeloid leukemia

Chronic myeloid leukemia(CML)is a hematopoietic myeloproliferative disorder.The Chinese prescription Danggui Longhui Wan(DGLHW)has been utilized in CML treatment,but its underlying mechanisms remain unclear.In this study,we gathered 794 constituents,1249 drug targets,1654 disease genes and 129 intersection genes.GO and KEGG were used to analyze the function of these genes.Compatibility of prescription study showed that monarch drug,minister drug,assistant and guide drug played a synergistic role in the treatment of CML.In addition,we obtained 20 hub genes and 12 key components.Molecular docking indicated that the main compounds and core proteins had good binding ability.The results of this study also showed that DGLHW might play a role in the treatment of CML by affecting MAPK,PI3K/AKT,FoxO and p53 signaling pathways.

Overexpression of P-glycoprotein induces acquired resistance to imatinib in chronic myelogenous leukemia cells

Imatinib,a breakpoint cluster region(BCR)-Abelson murine leukemia(ABL) tyrosine kinase inhibitor(TKI),has revolutionized the treatment of chronic myelogenous leukemia(CML).However,development of multidrug resistance(MDR) limits the use of imatinib.In the present study,we aimed to investigate the mechanisms of cellular resistance to imatinib in CML.Therefore,we established an imatinib-resistant human CML cell line(K562-imatinib) through a stepwise selection process.While characterizing the phenotype of these cells,we found that K562-imatinib cells were 124.6-fold more resistant to imatinib than parental K562 cells.In addition,these cells were cross-resistant to second-and third-generation BCR-ABL TKIs.Western blot analysis and reverse transcription-polymerase chain reaction(RT-PCR) demonstrated that P-glycoprotein(P-gp) and MDR1 mRNA levels were increased in K562-imatinib cells.In addition,accumulation of [14C]6-mercaptopurine(6-MP) was decreased,whereas the ATP-dependent efflux of [14C]6-MP and [3H]methotrexate transport were increased in K562-imatinib cells.These data suggest that the overexpression of P-gp may play a crucial role in acquired resistance to imatinib in CML K562-imatinib cells.

A Rare Entity of Accelerated Chronic Lymphocytic Leukemia: A Report of Two Cases and Review of Literature

Background: Accelerated-chronic lymphocytic leukemia (A-CLL) is a rare disease entity as it represents less than 1% of all reported cases of chronic lymphoid leukemia (CLL). Moreover, it is most likely an under diagnosed entity due to its rarity and the non-standardized practice of lymph node biopsy in CLL. Purpose: The aims of our work are to establish the diagnosis of A-CLL and to study the prognosis and treatment of this rare entity. Method: here, we report the clinical presentation and the follow up of two cases of A-CLL. Results: Distinguishing Richter transformation (RT) from A-CLL is important as it may result in a major change in disease management. The prognosis of A-CLL is intermediate between CLL and RT. The prognosis is mainly poor due to a predominance of poor prognostic markers including an increasing number of p53-positive cases. Conclusion: To this date, no prospective study has been led to define the best treatment for A-CLL. The shorter survival of A-CLL when compared to typical CLL implies the need of a more aggressive treatment.

RNF6 promotes chronic myelogenous leukemia cell proliferation and migration by stabilizing vimentin via multiple atypical ubiquitinations

Chronic myelogenous leukemia(CML)is a malignancy from bone marrow myeloid stem cells mainly driven by the fusion gene BCR-ABL.In addition to BCR-ABL,other genes including RNF6 are also dysregulated in CML cells.1 RNF6,a ubiquitin ligase of the RING family,promotes various cancer cell proliferation,chemoresistance,and tumor growth in vivo by targeting various proteins for ubiquitination and degradation,including SHP1,TLE3,FOXA1,and MAD1.^(2) However,its specific mechanism in CML is not known.

Co-existing squamous cell carcinoma and chronic myelomonocytic leukemia with ASXL1 and EZH2 gene mutations:A case report

BACKGROUND Chronic myelomonocytic leukemia(CMML),a rare clonal hematopoietic stem cell disorder characterized by myelodysplastic syndrome and myeloproliferative neoplasms,has a generally poor prognosis,and easily progresses to acute myeloid leukemia.The simultaneous incidence of hematologic malignancies and solid tumors is extremely low,and CMML coinciding with lung malignancies is even rarer.Here,we report a case of CMML,with ASXL1 and EZH2 gene mutations,combined with non-small cell lung cancer(lung squamous cell carcinoma).CASE SUMMARY A 63-year-old male,suffering from toothache accompanied by coughing,sputum,and bloody sputum for three months,was given a blood test after experiencing continuous bleeding resulting from a tooth extraction at a local hospital.Based on morphological results,the patient was diagnosed with CMML and bronchoscopy was performed in situ to confirm the diagnosis of squamous cell carcinoma in the lower lobe of the lung.After receiving azacitidine,programmed cell death protein 1,and platinum-based chemotherapy drugs,the patient developed severe myelosuppression and eventually fatal leukocyte stasis and dyspnea.CONCLUSION During the treatment and observation of CMML and be vigilant of the growth of multiple primary malignant tumors.

Unusual presentation of extramedullary blast crisis in chronic myeloid leukemia:A case report

BACKGROUND Extramedullary blast crisis in chronic myeloid leukemia(CML)is an uncommon occurrence of leukemic blast infiltration in regions other than the bone marrow.Malignant infiltration of the serosal membranes should be considered in cases where CML presents with ascites or pleural effusion.CASE SUMMARY A 23-year-old female with CML presented with progressively worsening ascites and pleural effusion despite first-line tyrosine kinase inhibitor treatment.Her blood work indicated leukocytosis with myelocyte bulge and 2%blasts.Analysis of the patient’s bone marrow confirmed the chronic phase of CML.Abdominal ultrasound revealed hepatosplenomegaly with ascites.The fluid investigation of both ascites and pleural effusion revealed a predominance of neutrophils with exudate.However,no acid-fast bacilli or growth was observed after culturing.Although hydroxyurea reduced cell counts,there was no observed effect on ascites or pleural effusion.Repeat investigation of the ascitic and pleural fluid revealed a polymorphous myeloid cell population consisting of myelocytes,metamyelocytes,band forms,neutrophils and a few myeloblasts.Extramedullary blast crisis was suspected,and mutation analysis was performed.We switched the patient to dasatinib.The patient’s symptoms were relieved,and ascites and pleural effusion diminished.CONCLUSION Serosal membrane involvement in CML is extremely rare.In this case,the patient responded well to dasatinib treatment.

Synchronous diagnosis and treatment of acute myeloid leukemia and chronic lymphocytic leukemia:Two case reports

BACKGROUND The concurrence of acute myeloid leukemia(AML)and chronic lymphocytic leukemia(CLL)is rare.Previous reports of such cases have focused mainly on clinical diagnosis and characteristics,so the mechanism remains unclear,and therapy options have been poorly explored.CASE SUMMARY Here,we report two cases of synchronous AML and CLL.Flow cytometry revealed two distinct abnormal cell populations(myeloblasts and lymphoid cells)according to scatter characteristics.CD5-positive B cell lymphoma with myeloid leukemia invasion was observed on lymph node biopsy.Chemotherapy regimens indicated for both AML and CLL were used in our patients,and our patients achieved complete response after chemotherapy.Next-generation sequencing of 88 genes was performed.CONCLUSION We conclude that early mutation and dysregulation at the hematopoietic stem cell stage and the accumulation of multiple rearrangements may cause the concurrence of CLL and AML.The treatment of infection and combination therapy aimed at the CLL component are significant in the management of patients with concurrent CLL and AML.

Construction,Expression and In Vitro Biological Behaviors of Ig scFv Fragment in Patients with Chronic B Cell Leukemia

The expression vector of SmIg scFv fragment was constructed in patient with B cell chronic lymphocyte leukemia （B-CLL） and expressed in E. coli to obtain scFv fragment, and the effect of the protein on the proliferation of stimulated peripheral blood mononuclear cells （PBMC） was investigated in vitro. Two pairs of primers were designed, and variable region genes of light chain and heavy chain were amplified by PCR respectively from the pGEM-T vectors previously constructed in our laboratory which containing light chain gene or Fd fragment of heavy chain gene. The PCR product was digested, purified and inserted into pHEN2 vector to construct the soluble expression vector pHEN2-scFv. After the induction by IPTG, the scFv protein was identified by SDS- PAGE electrophoresis and purified by Ni-NTA-Chromatography. MTT was used to determine the effect of purified protein on the proliferation of stimulated PBMC in vitro. Plasmid PCR and restriction enzyme digestion of pHEN2-scFv revealed the pHEN2-scFv vector was constructed successfully. Id-scFv protein was expressed in positive clone after induced by IPTG. SDS-PAGE analysis showed that the relative molecular weight of fusion protein was about 30 kD （1 kD= 0. 9921 ku）, which was consistent with the theoretically predicted value. Proliferation of PBMC could be induced by purified Id-scFv. It was suggested that the expression vector of SmIg scFv fragment was constructed successfully, and scFv protein was expressed and secreted from E. coil, which could induce proliferation of PBMC. This may lay an experimental foundation for further research of Id- HSP complex vaccine for B-CLL.

Gene Expression Pattern of Signal Transduction in Chronic Myeloid Leukemia

To explore the transcriptional gene expression profiles of signaling pathway in Chronic myeloid leukemia （CML）, a series of cDNA microarray chips were tested. The results showed that differentially expressed genes related to singal transduction in CML were screened out and the genes involved in Phosphoinositide 3-kinases （PI3K）, Ras-MAPK （mitogen-activated protein kinase） and other signaling pathway genes simultaneously. The results also showed that most of these genes were up-expression genes , which suggested that signal transduction be overactivated in CML. Further analysis of these differentially expressed signal transduction genes will be helpful to understand the molecular mechanism of CML and find new targets of treatment.

Mutation Analysis of IgVH Gene in B-Cell Chronic Lymphocytic Leukemia

Summary: The variable heavy chain region (VH) genes of 3 untreated patients with B cell chronic lymphocytic leukemia (B CLL) were cloned and analyzed. The VH family used was VH3 11, VH3 72 and VH3 33. More than 2 % difference from the corresponding germline gene was detected in all the 3 obtained potential functional genes (average 16.7). Mutation pattern analysis indicated evidence of antigen selective pressure observed in 1 of 3 cases. Our findings suggested that the tumor cells originate from post GC cells.

Eighty-year-old man with rare chronic neutrophilic leukemia caused by CSF3R T618I mutation:A case report and review of literature

BACKGROUNDChronic neutrophilic leukemia (CNL) is a rare bone marrow proliferative tumorand a heterogeneous disorder. In 2016, the World Health Organization includedactivating mutations in the CSF3R gene as one of the diagnostic criteria, withCSF3R T618I being the most common mutation. The disease is often accompaniedby splenomegaly, but no developmental abnormalities and significant reticularfibrosis, and no Ph chromosome and BCR-ABL fusion gene. So, it is difficult todiagnose at the first presentation in the absence of classical symptoms. Herein wedescribe a rare CNL patient without splenomegaly whose initial diagnostic cluewas neutrophilic hyperactivity.CASE SUMMARYThe patient is an 80-year-old Han Chinese man who presented with one month offatigue and fatigue aggravation in the last half of the month. He had nosplenomegaly, but had persistent hypofibrinogenemia, obvious skin bleeding, andhemoptysis, and required repeated infusion of fibrinogen therapy. After manyrelevant laboratory examinations, histopathological examination, and sequencinganalysis, the patient was finally diagnosed with CNL [CSF3R T618I positive:c.1853C>T (p.T618I) and c.2514T>A (p.C838)].CONCLUSIONThe physical examination and blood test for tumor-related genes are insufficientto establish a diagnosis of CNL. Splenomegaly is not that important, buthyperplasia of interstitial neutrophil system and activating mutations in CSF3Rare important clues to CNL diagnosis.

Horn of plenty:Value of the international registry for pediatric chronic myeloid leukemia

Chronic myeloid leukemia(CML)in minors is a rare disease which can be effectively treated by tyrosine kinase inhibitors(TKIs)since the year 2000.A majority of pediatricians will encounter one or two CML patients in the course of their careers and will typically have to rely on written information along with their own intuition to provide care.Knowledge of response to TKIs and of agespecific side effects has an impact on the design of pediatric CML trials in many ways aiming to contribute toward greater predictability of clinical improvements.Information from a registry on a rare disease like CML offers the enormous benefit of enabling treating physicians to interact and share their collective experience.The International Registry on Pediatric CML(IR-PCML)was founded at Poitiers/France almost 10 years ago.Since then,the number of collaboration centers and in parallel of registered patients continuously increased(>550 patients as of December 2019).Ideally,from a given treatment center in a country data are transferred to a national coordinator who interacts with the IR-PCML.In the sense of quality assurance,the registry can offer dissemination of knowledge on state-of-the-art diagnostics(including reference appraisal),optimal treatment approaches,and follow-up procedures within a network that is exerting its strength via participation.With continuous growth during the recent years,very rare subgroups of patients could be identified(e.g.,CML diagnosed at age<3 years,children presenting with specific problems at diagnosis or during course of treatment)which had not been described before.Publications coming from the IR-PCML disseminated this useful information derived from patients who robustly participate and share information about their disease,among themselves and with their caregivers and clinicians.Patient input driving the collection of data on this rare leukemia is the basis for the considerable success of bringing new therapeutics into clinical use.

Hepatitis B reactivation in chronic myeloid leukemia patients receiving tyrosine kinase inhibitor

Hepatitis B virus(HBV) reactivation is a well-recognized complication in patients with chronic HBV infection receiving cytotoxic or immunosuppressive chemotherapy.Imatinib mesylate and nilotinib are selective Bcr/Abl tyrosine kinase inhibitors,which are now widely used in the treatment of patients with chronic myeloid leukemia.Although HBV reactivation induced by imatinib mesylate has been reported,nilotinib-related HBV reactivation has not been reported in the English literature.We report here 2 cases of HBV reactivation in chronic myeloid leukemia patients receiving imatinib mesylate and a novel case of nilotinib related HBV reactivation.

Targeting chronic lymphocytic leukemia cells in the tumor microenviroment: A review of the in vitro and clinical trials to date

Chronic lymphocytic leukemia(CLL) is the most common leukemia in the western world. Despite significantadvances in therapy over the last decade CLL remains incurable. Current front-line therapy often consists of chemoimmunotherapy-based regimens, most commonly the fludarabine, cyclophosphamide plus rituximab combination, but rates of relapse and refractory disease are high among these patients. Several key signaling pathways are now known to mediate the survival and proliferation of CLL cells in vivo, the most notable of which are the pathways mediated by the B-cell receptor(BCR) and cytokine receptors. A better understanding of the pathogenesis of the disease, the underlying biology of the CLL-cell and the roles of the tumour microenvironment has provided the rationale for trials of a range of novel, more targeted therapeutic agents. In particular, clinical trials of ibrutinib and idelalisib, which target the Brutons tyrosine kinase and the delta isoform of phosphoinositol-3 kinase components of the BCR signaling pathway respectively, have shown extremely promising results. Here we review the current literature on the key signaling pathways and interactions of CLL cells that mediate the survival and proliferation of the leukemic cells. For each we describe the results of the recent clinical trials and in vitro studies of novel therapeutic agents.