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Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Atypical chronic myeloid leukemia (aCML) was initially described as a subtype of CML with the notable absence of the BCR-ABL1 fusion gene.142 Its diagnosis requires the exclusion of not only BCR-ABL1 but also rearrangement of PDGFRA, PDGFRB, or FGFR1. MPN-associated driver mutations such as JAK2, CALR, and MPL are typically absent in aCML. The differential diagnosis includes CNL, CMML, and MDS/MPN-U. Patients tend to have severe anemia, thrombocytopenia, neutrophilia with prominent granulocytic dysplasia, and splenomegaly; monocytosis and basophilia are usually absent or minimally present in the peripheral blood. There are some clinical and morphological similarities between aCML and CNL, which is typically associated with a mutated CSF3R gene, which is found in <10% of patients with aCML. Recurrent mutations have been described in SETBP1 and/or ETNK1 gene mutations in a third of cases, occasionally found in aCML. Allo-SCT appears to be the only treatment that can afford aCML patients a long-term remission.143 Other therapies include HMAs and hydroxycarbamide and the investigational use of JAK inhibitors.
Schinzel−Giedion Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
In contrast to germline variants that are responsible for the onset of SGS and increased risk for embryonal tumors, somatic SETBP1 mutations tend to occur in patients with hematologic neoplasms, including acute myeloid leukemia (AML, <1% of cases), myeloproliferative neoplasm (MPN, 4%), myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes (MDS/MPN, 9%), myelodysplastic syndrome (MDS, 2–3%), juvenile myelomonocytic leukemia (JMML, 8–10%), chronic myelomonocytic leukemia (CMML, 15–19%), chronic neutrophilic leukemia (CNL, 10–38%), and atypical chronic myeloid leukemia (aCML, 30%) [4–16]. Most cases are associated with heterozygous missense mutations, and only a few cases show a homozygous mutation. SETBP1 involvement in leukemia transformation is mainly through activation of the HOXA9 and HOXA10 genes, and subsequent increase in leukemic cell proliferation [17]. Somatic SETBP1 mutations observed in hematologic neoplasms appear to have a gain-of-function effect on the SETBP1 protein, leading to decreased binding of the βTrCP1 and increased protein levels. The somatic variants in hematologic neoplasms appear more disruptive than the germline variants in SGS, and patients with myeloid malignancies harboring SETBP1-mutations often have a significantly inferior overall survival and increased risk of disease progression [18–20].
Myelodysplastic/Myeloproliferative Diseases (Overlap Syndromes)
Published in Richard T. Silver, Ayalew Tefferi, Myeloproliferative Disorders, 2007
Bennett John M., Hanson Curtis A.
For at least four decades, hematologists and hematopathologists have distinguished two broad classes of chronic clonal hematopoietic neoplasms: those that are primarily dysplastic (increased rates of programmed cell death or apoptosis but often accompanied with a component of stem cell proliferation) referred to as the “myelodysplastic syndromes” (MDS) (1), and those that are primarily proliferative with a selective myeloid predominance that involves either the erythroid cell line [polycythemia vera (PV)]; granulocytic cell line [chronic myelogenous leukemia (CML), atypical chronic myeloid leukemia (aCML), chronic myelomonocytic leukemia (CMML), chronic eosinophilic leukemia, chronic neutrophilic leukemia, and juvenile myelomonocytic leukemia (JMML)]; and the megakaryocytic cell line [essential thrombocythemia (ET) and possibly primary myelofibrosis (PMF)] (2). As these diseases progress toward acute leukemia (often referred to as transformation), the morphologic common pathway includes dysplastic granulocytes and increased CD34+/117+ blasts. The identification, therefore, of a molecular abnormality such as BCR-ABL t(9;22) may be the only way to recognize the original chronic-phase diagnosis (3).
Systemic mastocytosis with myeloid sarcoma and B-CLL: molecular and clonal heterogeneity in a rare case of SM-AHN with review of literature
Published in Acta Clinica Belgica, 2023
Philippe Decruyenaere, Dominiek Mazure, Ine Moors, Jo Van Dorpe, Malaïka Van der Linden, Barbara Denys, Mattias Hofmans, Fritz Offner
Systemic mastocytosis with an associated hematological neoplasm (SM-AHN) comprises 40% of all reported SM cases [2]. SM-AHN is diagnosed when the WHO criteria for SM and a distinct hematologic neoplasm of non-mast cell lineage are met. For SM, WHO criteria distinguish between major (multifocal, dense infiltrates of mast cells in extra-cutaneous tissue), and minor criteria (atypical morphology or spindle shapes in >25% of MC on aspirate or biopsy; the presence of KITD816V mutation; aberrantly expressed CD25 and/or CD2; and an increased serum tryptase level). The diagnosis is made when the major and one minor criterion or three minor criteria are fulfilled. Importantly, increased serum tryptase level cannot be used as minor criterion for patients in which the AHN is a myeloid disorder [1]. In SM-AHN, an association with most hematologic neoplasms can be seen, although clonally related myeloid neoplasms are most frequently reported (89%) [1,2,4]. The most commonly associated myeloid-derived malignancies are chronic myelomonocytic leukemia (CMML), followed by myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), acute myeloid leukemia (AML), and Philadelphia-chromosome negative or atypical chronic myeloid leukemia (CML) [5]. The associated hematological non-mast cell lineage neoplasm may be diagnosed before, concurrently with, or after the diagnosis of SM. In this setting, it is important to underline that an otherwise well-defined myeloid malignancy, such as MDS or a non-MC MPN, might also harbor neoplastic MC, without fulfilling criteria for SM [6].
Myeloid neoplasm with ETV6::ACSl6 fusion: landscape of molecular and clinical features
Published in Hematology, 2022
Zhan Su, Xin Liu, Weiyu Hu, Jie Yang, Xiangcong Yin, Fang Hou, Yaqi Wang, Jinglian Zhang
In the WHO classification of tumors of hematopoietic and lymphoid tissues, there is a distinct type of myeloid neoplasm with a t(5;12)(q32;p13.2) karyotype, and the translocation forms an ETV6::PDGFRB fusion gene, which characterizes the disease entity of myeloid/lymphoid neoplasms with PDGFRB rearrangement. The hematological features of this entity are most often those of MDS/MPN or MPN, typically with eosinophilia, including chronic myelomonocytic leukemia (CMML, usually with eosinophilia), atypical chronic myeloid leukemia (aCML), BCR::ABL1-negative (usually with eosinophilia), and CEL, and some cases are classified into myeloproliferative neoplasms with eosinophilia (MPN-eos). TKIs exert therapeutic effects on MPNs with PDGFRB rearrangement [1]. However, another entity harboring the same t(5;12)(q32;p13.2) karyotype has been sporadically reported, in which the produced fusion gene is ETV6::ACSL6 rather than ETV6::PDGFRB. The patients carrying ETV6::ACSL6 share similar hematological features with those carrying ETV6::PDGFRB, although the former show no response to TKIs. Several variants of ETV6::ACSL6 have been found previously. Here, we report a male patient with chronic eosinophilic leukemia who experienced disease progression with poor curative effects. Moreover, a novel variant of ETV6::ACSL6 was identified. In addition, we reviewed the literature, collected a case series harboring the ETV6::ACSL6 fusion, and summarized the landscape of the disease, including genetic and clinical profiling, treatments and outcomes.
Hypereosinophilic syndromes in the precision medicine era: clinical, molecular aspects and therapeutic approaches (targeted therapies)
Published in Expert Review of Hematology, 2019
Alessandra Iurlo, Daniele Cattaneo, Umberto Gianelli
Hematological malignancies associated with PDGFRB rearrangement are less frequent [24,25]. Most patients with these fusions have been described as having a chronic MPN, MDS/MPN overlap neoplasm [e.g., chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML)], or rarely myeloid blast phase/secondary AML. This gene is located at chromosome 5q32, and the most common rearrangement is t(5;12)(q32;p13.2)/ETV6-PDGFRB. However, PDGFRB has been found rearranged to many other partner genes [26–30] and such fusions are considered as uncommon variants. Affected patients are usually adult men in their 50s [25,31–33]. Most hematological neoplasms associated with translocations of PDGFRB are sensitive to TKIs [34], and additional therapies are required only when patients present with acute leukemia or develop acute leukemia during follow-up.