The Philadelphia chromosome in leukemogenesis

The truncated chromosome 22 that results from the reciprocal translocation t(9;22)(q34;q11) is known as the Phila?delphia chromosome(Ph) and is a hallmark of chronic myeloid leukemia(CML).In leukemia cells,Ph not only impairs the physiological signaling pathways but also disrupts genomic stability.This aberrant fusion gene encodes the breakpoint cluster region?proto?oncogene tyrosine?protein kinase(BCR?ABL1) oncogenic protein with persistently enhanced tyrosine kinase activity.The kinase activity is responsible for maintaining proliferation,inhibiting differentia?tion,and conferring resistance to cell death.During the progression of CML from the chronic phase to the accelerated phase and then to the blast phase,the expression patterns of different BCR?ABL1 transcripts vary.Each BCR?ABL1 transcript is present in a distinct leukemia phenotype,which predicts both response to therapy and clinical outcome.Besides CML,the Ph is found in acute lymphoblastic leukemia,acute myeloid leukemia,and mixed?phenotype acute leukemia.Here,we provide an overview of the clinical presentation and cellular biology of different phenotypes of Ph?positive leukemia and highlight key findings regarding leukemogenesis.

Chronic myeloid leukemia-from the Philadelphia chromosome to specific target drugs:A literature review

Chronic myeloid leukemia(CML)is a myeloproliferative neoplasm and was the first neoplastic disease associated with a well-defined genotypic anomaly―the presence of the Philadelphia chromosome.The advances in cytogenetic and molecular assays are of great importance to the diagnosis,prognosis,treatment,and monitoring of CML.The discovery of the breakpoint cluster region(BCR)-Abelson murine leukemia(ABL)1 fusion oncogene has revolutionized the treatment of CML patients by allowing the development of targeted drugs that inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein.Tyrosine kinase inhibitors(known as TKIs)are the standard therapy for CML and greatly increase the survival rates,despite adverse effects and the odds of residual disease after discontinuation of treatment.As therapeutic alternatives,the subsequent TKIs lead to faster and deeper molecular remissions;however,with the emergence of resistance to these drugs,immunotherapy appears as an alternative,which may have a cure potential in these patients.Against this background,this article aims at providing an overview on CML clinical management and a summary on the main targeted drugs available in that context.

Administration of imatinib in the first 90 days after allogeneic hematopoietic cell transplantation in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

Background Relapse happens frequently after allogeneic hematopoietic cell transplantation （alIo-HCT） in the patients with Philadelphia chromosome-positive acute lymphoblastic leukemia （Ph^＋ ALL）. Detection of the minimal residual disease （MRD） before and after alIo-HCT is associated with higher relapse rate. Early administration of imatinib after alIo-HCT may prevent recurrent Ph^＋ ALL. The aim of this study was to evaluate the safety and efficacy of imatinib in preventing hematological relapse when imatinib was administrated in the first 90 days after alIo-HCT. Methods Patients with Ph^＋ ALL that underwent alIo-HCT were enrolled in a prospective study. A TaqMan-based real-time quantitative polymerase chain reaction （RQ-PCR） technique was used to detect the MRD （bcr-abl transcript levels）. Imatinib therapy was initiated prior to 90 days after alIo-HCT if the patient＇s absolute neutrophil count （ANC） was above 1.0×10^9/L （without granulocyte colony-stimulating factor （G-CSF） administration） and the platelet count was greater than 50.0×10^9/L, or if the bcr-abl transcript levels were elevated in two consecutive tests, or if the bcr-abl transcript levels were 〉10.2 after the initial engraftment. The initial daily dose of imatinib was 400 mg/d for adults and 260 mg/m^2 for children （younger than 17 years）. Imatinib was administered for at least I month and the bcr-abl TaqMan results were negative for 3 consecutive tests, or complete molecular remission （CR^mol） was sustained for at least 3 months. Results From May 2005 to October 2008, 29 patients were enrolled in this study, of whom, 19 patients were male and 10 were female. The median age of the enrolled patients was 33 years （range 6-50 years）. Imatinib therapy was started at a median time of 60 days （range 20-122 days） post HCT （only one patient started Imatinib therapy at 122nd day after HCT）. Twenty-five adult patients could tolerate a dose of 300-400 mg/d of imatinib, and three children tolerated a dose of 260 mg·m^2·d^-1. Sixty-eight percent of the patients experienced various adverse events during imatinib therapy, hematological toxicity being the most common adverse event. The median duration of imatinib treatment was 3 months （range 7 days-18 months）. During the median follow-up of 24 months （range 16.0-54.5 months）, 3 out of 27 patients that could be evaluated for efficacy died from relapse. The 3-year probability of relapse for the evaluated patients was （11.34-0.61）%. The relapse rates among the subgroup of positive and negative bcr-abl patients before allo-HCT were 13.6% and 0, respectively （P 〉0.05）. The relapse rates among the subgroups of bcr-abl positive and negative patients after alIo-HCT were 20.0% and 5.9%, respectively （P 〉0.05）. The relapse rates among the patients in first complete remission （CR1） and second complete remission/non-remission （CR2/NR） before transplantation were 0 and 31.4%, respectively （P 〈0.05）. The 3-year probability of overall survival （OS） and disease-free survival （DFS） for the all enrolled patients were （75.3±8.1）%. The 3-year probabilities for OS and DFS among the subgroup of patients in CR1 and CR2/NR before transplantation were （87.7±8.2）% and （54.6±15.0）%, respectively （P 〈0.05）. Conclusions Administration of irnatinib at a dose of 300-400 mg/d in the first 90 days after allo-HCT is feasible in Ph^＋ ALL patients. With this treatment, bcr-abl positive patients before or after transplantation do not have a higher relapse rate after allo-HCT compared with the bcr-abl negative patients. Because of lower relapse rate and better OS and DFS, we recommend that Ph^＋ ALL patients receive allo-HCT in CRI.

Efficacy and prognostic factors of imatinib plus CALLG2008 protocol in adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia

A CALLG2008 protocol was developed by the Chinese Acute Lymphoblastic Leukemia Cooperative Group for adult acute lymphoblastic leukemia （ALL）. We retrospectively analyzed 153 newly diagnosed adult patients with Philadelphia chromosome （Ph）-positive ALL enrolled into imatinib （400 mg/d） plus CALLG2008 regimen between 2009 and 2015. The median age was 40 years （range, 18-68 years）, with 81 （52.3%） males. The overall hematologic complete remission （CR） rate was 96.7% after induction. With a median follow-up of 24.2 months, the estimated 3-year overall survival （OS） and event-free survival （EFS） rates were 49.5% （95% confidence interval （CI）： 38.5%-59.5%） and 49.2% （95% CI： 38.3%-59.2%）, respectively. Fifty-eight （36 with haploidentical donor） patients underwent allogeneic hematopoietic stem call transplantation （allo-HSCT） in first CR. Among the patients in CR1 after induction, both the 3-year OS and EFS were significantly better in the allo-HSCT group than in the without alIo-HSCT group （73.2%, 95% CI： 58.3%-83.5% vs. 22.2%, 95% CI： 8.7%-39.6% and 66.5%, 95% CI： 50.7%-78.2% vs. 16.1%, 95% CI： 5.1%-32.7%, respectively）. Multivariate analysis showed that alIo-HSCT and achievement of major molecular response were associated with favorable OS or EFS independently. Interestingly, in the alIo-HSCT cohort, the donor type （haploidentical versus matched donors） had no significant impact on EFS or OS. All these results suggested that imatinib plus CALLG2008 was an effective protocol for Ph-positive ALL. Haploidentical donors can also be a reasonable alternative expedient donor pool.

Philadelphia chromosome-positive acute myeloid leukemia with masses and osteolytic lesions： finding of 18F-FDG PET/CT

Philadelphia chromosome-positive acute myeloid leukemia is controversial and difficult to distinguish from the blast phase of chronic myeloid leukemia. As a myeloid neoplasm, rare cases of this leukemia manifest multiple soft-tissue tumors or bone lyric lesions. In this paper, we describe a 49-year-old male patient who had an abrupt onset with sharp chest pain, fever, fatigue, emaciation, and splenomegaly. 18F-fluoro-deoxy-glucose positron emission tomography/computed tomography （18F-FDG PET/CT） result showed diffuse and uneven hypermetabolic lesions in the bone marrow with peripheral bone marrow expansion, multiple soft tissue neoplasms with high 18F-FDG uptake, and lyric bone lesions. Bone marrow smear and biopsy detected aberrant blast cells expressing myeloid rather than lymphoid immunophenotype marker. For the existence of Philadelphia chromosome and BCR-ABL1 fusion gene together with complex chromosome abnormalities, a diagnosis of Philadelphia-positive acute myeloid leukemia was made, although the type （de novo or blast crisis） remained unclear.

Damage Mechanism of CK2 and IKAROS in Philadelphia Like Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is characterized by immature and poorly differentiated B lymphocytes in large numbers in the blood. B cells are distinct from the cell types involved in their development (common lymphoid progenitor cells, pro-B cells, pre-B cells, and mature cells). The process of B cell maturation depends on precise communication within the cell: signals activate specific genes that are essential for proper development. Errors in this intricate signaling network can lead to issues with B cell function and contribute to disease. B-lineage acute lymphoid leukemias, malignancies of precursor-stage B lymphoid cells inhibit lymphoid differentiation, leading to abnormal cell proliferation and survival. The process of developing leukemia (leukemogenesis) can be triggered by an overproduction of both hematopoietic stem cells (the cells that form all blood cells) and the immature versions of white blood cells called lymphoblasts. Acute lymphoblastic leukemia (ALL) with the presence of the Philadelphia chromosome (ALL Ph) is classified as a high-risk manifestation of the disease, this chromosome is the product of the reciprocal translocation, whose product is a BCR-ABL fusion protein. It is a highly active tyrosine kinase that can transform hematopoietic cells into cytokine-independent. Hyperphosphorylation cascades inhibit the differentiating function of IKZF1 as a tumor suppressor gene which leads to an abnormal proliferation of B cells due to the presence of the Philadelphia chromosome;it inhibits the differentiating process, leukemogenesis involving immature B cells in the bloodstream can result from the uncontrolled growth and division of hematopoietic stem cells and immature lymphoblasts (the precursors to B cells).

A novel t(3;12)(q21;p13) translocation in a patient with accelerated chronic myeloid leukemia after imatinib and nilotinib therapy

The acquisition of secondary chromosomal aberrations in chronic myeloid leukemia (CML) patients with Philadelphia chromosome-positive (Ph+) karyotype signifies clonal evolution associated with the progression of the disease to its accelerated or blastic phase. Therefore, these aberrations have clinical and biological significance. T(3;12)(q26;p13), which is a recurrent chromosomal aberration observed in myeloid malignancies, is typically associated with dysplasia of megakaryocytes, multilineage involvement, short duration of any blastic phase, and extremely poor prognosis. We have identified a recurrent reciprocal translocation between chromosomes 3 and 12 with different breakpoint at bands 3q21 in the malignant cells from a 28-year-old man. The patient was initially diagnosed as having Ph+ CML in the chronic phase. The t(3;12)(q21;p13) translocation occurred 4 years after the patient was first diagnosed with CML while undergoing tyrosine kinase inhibitor therapy. We confirmed the t(3;12)(q21;p13) translocation via fluorescence in situ hybridization assay by using whole-chromosome paint probes for chromosomes 3 and 12. Our findings demonstrate that, similar to other recurrent translocations involving 3q26 such as t(3;3) and t(3;21), the t(3;12)(q21;p13) translocation is implicated not only in myelodysplastic syndrome and acute myeloid leukemia but also in the progression of CML. These findings extend the disease spectrum of this cytogenetic aberration.

Acute Priapism: A Revealing Inaugural Mode of Chronic Myeloid Leukemia. A Case Report and Review of the Literature

Priapism is a painful and prolonged erection occurring without any sexual stimulation and not resulting in ejaculation. It most often occurs in patients with sickle cell disease. We report here the case of acute recurrent priapism revealing inaugural mode of CML in a 22-year-old patient with no particular pathological history. The study of the onco-hematological karyotype revealed a karyotype with 46 chromosomes with a clonal chromosomal anomaly: The t (9;22) “Philadelphia chromosome”. The evolution was favorable under imatinib.

Clonal evolution analyses of a chronic myeloid leukemia patient with hematopoietic stem cell transplantation based on deep sequencing

Background The Philadelphia(Ph)chromosome is the hallmark chromosome aberration in chronic myeloid leukemia(CML),which confers the cancer phenotype of the disease.However,how the Ph chromosome forms and the genetic clonal evolution structure after targeted Ph treatment are still unclear.Methods In this study,we performed genome sequencing and clonal evolution analyses in a series of bone marrow specimens and skin biopsy from a CML patient who had received hematopoietic stem cell transplantation from her sister,then relapsed(lymphoid blast crisis),and received Ph-targeted therapy.Results The Ph chromosome was the“driver”clonal change in the original CML and the relapse.Both the patient and her sister had micro-deletions in the BCR gene region;however,the patient had a frameshift BRIP1 mutation that may account for the malfunctioning homologous recombination DNA repair of the BCR gene region and formation of the Ph chromosome.Conclusion We found that the BCR-ABL1 translocation was the driving force of the patient’s CML and relapse.The malfunctioning double-strand DNA break repair caused by the BRIP1 mutation could be the cause of Ph chromosome formation in the patient.