Atypical Myeloproliferative Disorder Research Articles

Clonal Megakaryocyte Dysplasia with Normal Blood Values Is a Distinct Myeloproliferative Neoplasm

Introduction: In 1991, we reported 18 persons with a clinical-pathologic entity and termed atypical myeloproliferative disorder because they did not meet the contemporary diagnostic criteria for a myeloproliferative neoplasm. We sought to gain further knowledge on this disease entity. Methods: This retrospective cohort study included consecutive subjects registered in the database of the Center for the Study of Myelofibrosis in Pavia, Italy, from 1998 to 2020 (June), and diagnosed with atypical myeloproliferative disorder according to our adjudicated criteria. We studied clinical, histological, cytogenetic, and molecular covariates and risks of thrombosis, disease progression, and death. Data were compared with those of concurrent subjects with prefibrotic myelofibrosis. Results: Fifteen new subjects with atypical myeloproliferative disorder were identified. Seven were male. Median age was 50 years (IQR, 41–54 years). Thirteen were diagnosed with a synchronous symptomatic or incidentally detected thrombotic event. The bone marrow showed megakaryocyte hyperplasia with dysplasia. JAK2V617F was present in 10 subjects and CALR mutation in one. No other somatic mutations were identified in next generation sequencing. After a median follow-up of 101 months (IQR, 40–160 months), no subject had disease progression or blast transformation. Incidence of post-diagnosis or recurrent thrombosis was 3.9 events (95% confidence interval, 3.5–4.0) and 5.0 events (4.6–5.6) per 100 person-years. Features of subjects with atypical myeloproliferative disorder differed markedly from those of 546 subjects with prefibrotic myelofibrosis. Conclusion: Our data indicate that these 15 persons have a distinct myeloproliferative neoplasm. We propose naming this new disorder clonal megakaryocyte dysplasia with normal blood values.

Issue Highlights—May 2013

Issue Highlights—May 2013

Acute Progression of BCR-FGFR1 Induced Murine B-Lympho/Myeloproliferative Disorder Suggests Involvement of Lineages at the Pro-B Cell Stage

Constitutive activation of FGFR1, through rearrangement with various dimerization domains, leads to atypical myeloproliferative disorders where, although T cell lymphoma are common, the BCR-FGFR1 chimeric kinase results in CML-like leukemia. As with the human disease, mouse bone marrow transduction/transplantation with BCR-FGFR1 leads to CML-like myeloproliferation as well as B-cell leukemia/lymphoma. The murine disease described in this report is virtually identical to the human disease in that both showed bi-lineage involvement of myeloid and B-cells, splenomegaly, leukocytosis and bone marrow hypercellularity. A CD19+ IgM− CD43+ immunophenotype was seen both in primary tumors and two cell lines derived from these tumors. In all primary tumors, subpopulations of these CD19+ IgM− CD43+ were also either B220+ or B220−, suggesting a block in differentiation at the pro-B cell stage. The B220− phenotype was retained in one of the cell lines while the other was B220+. When the two cell lines were transplanted into syngeneic mice, all animals developed the same B-lymphoblastic leukemia within 2-weeks. Thus, the murine model described here closely mimics the human disease with bilineage myeloid and B-cell leukemia/lymphoma which provides a representative model to investigate therapeutic intervention and a better understanding of the etiology of the disease.

Atypical Myeloproliferative Disorders: Diagnosis and Management

Atypical Myeloproliferative Disorders: Diagnosis and Management

Atypical myeloproliferative disorders in adults

The definition of ‘atypical MPDs’ includes all chronic myeloid disorders that defy classification as either MDS or classic MPDs. These can be both molecularly defined or clinicopathologically assigned: chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, chronic neutrophilic leukemia, chronic basophilic leukemia, chronic eosinophilic leukemia, idiopathic eosinophilia including hypereosinophilic syndrome, systemic mastocytosis, unclassified MPD, and eosinophilic/mast cell disorders associated with mutations of PDGFR, FGFR1, and KIT all fall under the category of atypical MPDs.

From Vaquez to Dameshek through JAK…2 much for polycythemia vera to be feared?

Clinical practice in modern medicine is a gift that comes from afar. It comes sometimes from a lucky discovery, or sometimes from brave attempt chasing what at that time seemed crazy theories. Anyway, the gift we currently enjoy is the result of careful observation at first, and then like a sculptor with his chisel that free from marble an hidden figure, doctors and researchers carve during the years the features of many diseases. In this number of the Internal and Emergency Medicine Journal, Landolfi and his co-workers [1] reviewed the principal characteristics of polycythemia vera (PV), starting from the history of the first published description by Luis Henry Vaquez in 1892 [2]. Since this first description something other than plethora and cyanosis were soon identified: the high risk of major thrombotic events potentially leading to death, both in arterial district (acute myocardial infarction, stroke or transient ischemic attack, TIA), and in venous district (deep vein thrombosis, pulmonary embolism, and splanchnic thrombosis). The mortality rate of PV, as reassessed in the ECLAP study [3] is about 3.7/100 patients/year due not only to the vascular complications but also for a possible evolution to malignancy. The history of PV went through the recognition of an absolute increase of blood cells, due to an abnormal erythropoiesis as the result of a pluripotential stem cell being erythropoietin hypersensitive and independent [4]. The related clinical condition must be differentiated from secondary erythrocytosis and this exercise has challenged haematologist for decades. So, like industrious sculptors, haematologist has learnt to use diagnostic criteria like chisels to carve for each patient the hidden truth of primary or secondary hyperglobulia. But not all sculptors are the same. Amedeo Modigliani, the great painter and sculptor used to say that he could see at a glance what was inside a piece of marble, and that he just had to free it. In the same way, Dameshek [5] in 1951 described his vision ‘‘from outside’’ and speculated that PV has the same origin of essential thrombocythemia (ET), chronic idiopathic myelofibrosis (IMF) and chronic myeloid leukemia (CML). What was really inside, and Dameshek had seen, was proved more than 50 years later with the discovery of the mutation at position 617 in the JH2 domain of the Janus Kinase 2 (JAK2) cytoplasmic tyrosine kinase [6–9]. This gainof-function mutation, recognizable in almost 90% of PV patients, is acquired and present in clonal hemopoietic stem cells and responsible for the activation of Epo-signaling pathway, leading to hypersensitivity and uncontrolled growth of cells. The JAK2V617F mutation is also found in about 50% of patients with ET and IMF, in atypical myeloproliferative disorders, but it has been described also in some patients with CML and in patients with portal vein thrombosis but without hematological abnormalities. From these observation, recent theories and hypothesis have been explained, such as different intensity of JAK2 signaling, presence of pre-JAK2 event that will result in different myeloproliferative disorders, different host modifier polymorphisms [10], just to cite some of them. M. Carpenedo (&) E. M. Pogliani Hematology and Bone Marrow Transplantation Unit, San Gerardo Hospital, University of Milan Bicocca, Via Pergolesi 33, 20035 Monza, Italy e-mail: mcarpenedo@katamail.com

Errata: Phosphorylation of the SSBP2 and ABL proteins by the ZNF198‐FGFR1 fusion kinase seen in atypical myeloproliferative disorders as revealed by phosphopeptidespecific MS

Errata: Phosphorylation of the SSBP2 and ABL proteins by the ZNF198‐FGFR1 fusion kinase seen in atypical myeloproliferative disorders as revealed by phosphopeptidespecific MS

Genetic fingerprinting of the development and progression of T-cell lymphoma in a murine model of atypical myeloproliferative disorder initiated by the ZNF198–fibroblast growth factor receptor-1 chimeric tyrosine kinase

AbstractA mouse model of human ZNF198–fibroblast growth factor receptor-1 (FGFR1) stem cell leukemia lymphoma has been developed to investigate mechanisms of oncogenesis and progression. Using array-based comparative genomic hybridization, we followed disease progression after serial transplantation of ZNF198-FGFR1–transformed stem cells that give rise to a distinct myeloproliferative disorder and T-lymphoblastic leukemia. A consistent, frequently homozygous, chr14:53880459-55011545 deletion, containing the T-cell receptor α and δ genes, was identified in the bone marrow, spleen, and lymph nodes in all cases. The absence of cell-surface T-cell receptor α in tumor cells precludes CD3 recruitment, resulting in loss of a functional T-cell receptor complex, supporting the idea that prevention of maturation of CD4+/CD8+ double-positive immature T cells is important in ZNF198-FGFR1 disease development. Up-regulation of the B-cell line 2, interleukin 7 receptor α and interleuking 2 receptor α prosurvival genes in these undifferentiated tumor precursor cells suggests one mechanism that allows them to escape apoptosis in the thymus. Thus, we have defined an important event in the process of ZNF198-FGFR1–induced T-cell leukemia.

Phosphorylation of the SSBP2 and ABL proteins by the ZNF198‐FGFR1 fusion kinase seen in atypical myeloproliferative disorders as revealed by phosphopeptide‐specific MS

The ZNF198-fibroblast growth factor receptor-1 (FGFR1) fusion kinase is a constitutively activated tyrosine kinase associated with a specific atypical myeloproliferative disease. The chimeric protein localizes to the cytoplasm, unlike the wild type FGFR1 receptor kinase, and presumably inappropriately phosphorylates specific targets as part of the oncogenic signaling cascade. Other than known targets of the FGFR1 kinase itself, few specific targets of ZNF198-FGFR1 have been identified. Using a genetically engineered HEK 293 cell system, we have identified proteins that are specifically phosphorylated in the presence of the fusion kinase using anti-phosphotyrosine immunoprecipitation and MS. Compared with 293 cells expressing exongenous wild type FGFR1, ZNF198-FGFR1 is associated with phosphorylation of several proteins including SSBP2, ABL, FLJ14235, CALM and TRIM4 proteins. The specificity of the phosphorylation events in the SSBP2 and ABL proteins, which have previously been implicated in leukemogenesis, was further confirmed independently using immunoprecipitation with protein-specific antibodies and Western blotting. The MS analysis also identified the phosphorylation events in the ZNF198 moiety in the chimeric protein that might be related to its function. These studies identify the intersection of several different leukemia-related pathways in the development of this myeloproliferative disorder and provide new insights into the substrates of FGFR1 under defined conditions.

Fibroblast Growth Factor Receptor and Platelet-Derived Growth Factor Receptor Abnormalities in Eosinophilic Myeloproliferative Disorders

Rearrangements of the genes encoding the fibroblast growth factor receptor 1 (FGFR1) and platelet-derived growth factor receptors (PDGFR) α or β receptor tyrosine kinases are found in a rare but important subset of patients with atypical myeloproliferative disorders that are usually but not always associated with eosinophilia. Chromosomal translocations or other rearrangements at 8p11–12, 4q12 or 5q31–33 give rise to diverse fusion genes encoding chimaeric proteins with constitutive transforming activity. There is considerable molecular heterogeneity with 8 partner genes currently known for FGFR1, 6 for PDGFRA and 17 for PDGFRB. The vast majority of patients with PDGFRA or PDGFRB fusions achieve rapid and durable complete haematological and molecular responses to sustained imatinib therapy. A key ongoing challenge is to define the molecular pathogenesis of the great majority of atypical myeloproliferative disorders for whom the causative lesion remains unknown, since very few of these cases gain any benefit from imatinib or other second-generation inhibitors.

Undiagnosed Myeloproliferative Disease in Cases of Intra-Abdominal Thrombosis: The Utility of the JAK2 617F Mutation

Extrahepatic portal vein thrombosis and Budd-Chiari syndrome frequently result from multiple concurrent factors such as cirrhosis, intra-abdominal sepsis, procoagulant states, and underlying myeloproliferative disorders (MPDs). The JAK2 V617F mutation is a point mutation in the Janus kinase 2 (JAK2) tyrosine kinase that is variably present in MPDs. The incidence depends on the subclassification of the MPDs and the sensitivity of the assay used. This case series aimed to illustrate the diagnostic utility of JAK2 V617F mutation in atypical cases of MPD that otherwise may not have met traditional diagnostic criteria. Granulocytic DNA was obtained and real-time polymerase chain reaction was performed using allele-specific primer and probe to provide a quantitative expression of the V617F mutation. The JAK2 V617F point mutation was found in 3 patients with extrahepatic portal vein thrombosis who had multiple thrombotic events but did not fulfill the traditional diagnostic criteria for MPDs. A sensitive assay for the JAK2 V617F mutation has the potential to diagnose atypical MPDs in multiple undiagnosed cases of intra-abdominal thrombosis and therefore alter the management and prognosis of these patients.

Fusion of PRKG2 and SPTBN1 to the platelet-derived growth factor receptor beta gene ( PDGFRB) in imatinib-responsive atypical myeloproliferative disorders

Chromosomal translocations involving the platelet-derived growth factor receptor beta gene ( PDGFRB) have been reported in a subset of patients with atypical myeloproliferative disorders (MPDs). The fusion of the PDGFRB gene, which encodes a tyrosine kinase receptor, with different partner genes results in its constitutive activation. We present the cases of two patients with atypical MPD carrying t(4;5)(q21;q33) and t(2;5)(p21;q33), respectively. Fluorescence in situ hybridization demonstrated that PDGFRB was involved in both translocations. Further characterization of the 4q21 breakpoint using a bacterial artificial chromosome probe revealed PRKG2 as the likely gene partner to PDGFRB. Characterization of the 2p21 breakpoint identified a novel gene partner to PDGFRB, the SPTBN1 gene. Both patients achieved a complete molecular remission after introduction of imatinib mesylate therapy.

Mayo Clinic Proceedings 2008: Content Refinement, Continuing Medical Education Credit, Web Site Improvements, and More

Mayo Clinic Proceedings 2008: Content Refinement, Continuing Medical Education Credit, Web Site Improvements, and More

Rapid transformation of atypical myeloproliferative disorder with consistent t(8;13) to B-cell acute lymphoblastic leukemia: A case report

8p11 myeloproliferative syndrome (EMS; also known as the stem cell leukemia syndrome-SCLL) is a rare atypical myeloproliferative disorder associated with chromosomal abnormalities involving the 8p11 chromosomal band. Translocations associated with this syndrome result in the fusion of the fibroblast growth factor receptor 1 (FGFR 1) gene with various partners, resulting in ligand independent FGFR activity. The most commonly observed translocation of this syndrome is t(8;13), which results in the expression of a chimeric ZNF198-FGFR1 tyrosine kinase. Disease phenotype associated with this translocation has some typical features such as poor prognosis, and transformation to mainly acute leukemia and non-Hodgkin lymphoma; commonly with a T-cell phenotype in which obtaining and maintenance of remission is difficult by conventional chemotherapy. We hereby present a case diagnosed as atypical chronic myeloproliferative disease with consistent t(8;13)(p12;q12) and transformed rapidly to pre-B-cell acute lymphoblastic leukemia which is a rare clinical presentation.

Rearrangements involving 12q in myeloproliferative disorders: possible role of HMGA2 and SOCS2 genes

We report two cases of translocation associated with deletion on derivative chromosomes in atypical myeloproliferative disorder (MPD). In a MPD with t(3;12)(q29;q14), the rearrangement targeted the HMGA2 locus at 12q14 and deleted a region of about 1.5 megabases (Mb) at 3q29. In an MPD with t(9;12)(q13∼q21;q22) and JAK2 V617F mutation, array comparative genomic hybridization delineated a deletion of about 3 Mb at 9q13∼q21 and a deletion of about 2 Mb at 12q22 containing SOCS2. These results show that close examination of translocations in hematopoietic diseases may reveal associated microdeletions. The role of these deletions is discussed.

Atypical Chronic Myeloproliferative Disorders: Genes and Imatinib-Sensitive Targets

Acrucial step in development of rationally designed agents to treat cancer is the identification of target molecules responsible for neoplastic proliferation. Unfortunately, identification of critical targets has been a stumbling block to therapeutic breakthroughs for the vast majority of cancers. Notable exceptions are chronic myeloid leukemia (CML), gastrointestinal stromal tumor (GIST), and certain types of breast and lung cancer. 1 Agents that target the specific tyrosine kinase oncogene on which these malignant cells depend have vindicated the targeted approach to cancer therapy. 2 An unexpected consequence of the success of targeted therapy has been the basic science discoveries of disease pathogenesis for which clinical efficacy in investigational settings has, on occasion, provided the impetus. 3 These observations strengthen the rationale for targeted therapy in diseases where efficacy is demonstrated, but where no target has yet been identified, and raise awareness of the potential for novel genetic aberrations underlying disease. This supplement contains two review articles summarizing the rationale for treatment of certain atypical myeloproliferative diseases with the tyrosine kinase inhibitor imatinib (Glivec ® , Novartis, Basel, Switzerland). In my article, “Hypereosinophilicsyndromeandmolecularlytargetedther

WHO bone marrow features and European clinical, molecular, and pathological (ECMP) criteria for the diagnosis of myeloproliferative disorders

The bone marrow criteria defined by the World Health Organization (WHO) are based on characteristic increase and clustering of morphologically abnormal enlarged megakaryocytes as a pathognomonic clue to describe three distinct phenotypic entities of myeloproliferative disorders (MPDs): (1) essential thrombocythemia (ET), (2) early and overt polycythemia vera (PV) and (3) prefibrotic, early fibrotic, and fibrotic chronic idiopathic myelofibrosis (CIMF-0, 1, 2 and 3). Based on established WHO bone marrow features, and the use of new molecular and laboratory markers including JAK2 V617F mutation, endogenous erythroid colony (EEC) formation and serum erythropoietin (EPO), we present updated European clinical, molecular and pathological (ECMP) criteria for the differential diagnosis of true ET, PV and CIMF. As compared to the WHO bone marrow features, each of the laboratory and molecular markers are not sensitive enough for the diagnosis and classification of the three prefibrotic MPDs. The proposed WHO/ECMP criteria reduce the platelet count to the upper limit of normal (>400 × 10 9 l −1) as inclusion criterion for the diagnosis of thrombocythemia in true ET, early stages of PV and prefibrotic CIMF. The combined use of WHO and ECMP criteria differentiate PV from congenital and acquired erythrocytosis, true ET from reactive thrombocytosis and separates true ET from CIMF-0/1 mimicking ET. Only half of the patients with true ET and CIMF carry the JAK2 V617F mutation (sensitivity 50%). Early PV mimicking ET is featured by the presence of JAK2 V617F mutation, EEC, low serum EPO levels, normal hematocrit, and increased bone marrow cellularity due to increased erythropoiesis (“forme fruste” PV) when WHO/ECMP criteria are applied. The combination of JAK2 V617F PCR test and increased hematocrit is diagnostic for PV (sensitivity 95%, specificity 100%). The degree of JAK2 V617F positivity of granulocytes is related to disease stage: heterozygous in true ET and early PV and mixed hetero/homozygous to homozygous in overt and advanced PV and CIMF. Bone marrow histology assessment should remain the gold standard criterion for the diagnosis and staging of the MPDs true ET, PV and CIMF and its differentiation from primary or secondary erythrocytosis, reactive thrombocytosis and thrombocythemias associated with atypical MPD, myelodysplastic syndromes, and chronic myeloid leukemia,. The proposed WHO/ECMP criteria allow a cross talk between clinicians, pathologists and scientists to much better characterize the nature and natural history of each of the WHO/CMP defined early and overt MPDs.

Myelofibrosis with a novel translocation, t(1;3)(q31;q23), and response to imatinib mesylate

Imatinib mesylate is a tyrosine kinase inhibitor with preferential activity toward the bcr-abl fusion protein of chronic myelogenous leukemia (CML).1 Imatinib mesylate is also active against a limited number of other tyrosine kinases, including c-kit, PDGFR and PDGFR.2 Significant clinical activity has been demonstrated in diseases in which these tyrosine kinases play a major role, including a variety of myeloproliferative disorders such as the hypereosinophilic syndromes.3 Currently, we report on a patient with an atypical myeloproliferative disorder and a novel balanced translocation who had a dramatic clinical response to imatinib mesylate. The specific target in this patient is unknown.

Acute leukaemoid reaction following cardiac surgery

Chronic myelomonocytic leukaemia is an atypical myeloproliferative disorder with a natural history of progression to acute myeloid leukaemia, a complex and poorly understood response by the bone marrow to stress. Cardiac surgery activates many inflammatory cascades and may precipitate a systemic inflammatory response syndrome. We present a case of undiagnosed chronic myelomonocytic leukaemia who developed rapidly fatal multi-organ dysfunction following cardiac surgery due to an acute leukaemoid reaction.

Mayo Clinic Proceedings 2007: Enriching Our Service to Authors and Readers

Mayo Clinic Proceedings 2007: Enriching Our Service to Authors and Readers