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Myelodysplastic Syndromes (MDS)
Published in Dongyou Liu, Tumors and Cancers, 2017
Molecularly, MDS is linked to cytogenetic abnormalities (e.g., deletions of the long arm of chromosome 5 [del5q, affecting the q31 to q33 bands], monosomy Y, monosomy 7 [del7] or its long arm [del7q], trisomy 8, and del20q); genetic alterations involving DNA methylation (TET2 [on 4q24, 21% cases] DNMT3A, IDH2 [on 15q26, 2% cases], IDH1 [on 2Q33, 1% cases]), post-translational chromatin modification (ASXL1 [on 20q11, 14% cases], EZH2 [on 7q36, 6% cases]), RNA spliceosome machinery (SF3B1 [on 2q33, 28% cases], SRSF2 [on 17q25, 12% cases], ZRSR2, U2AF1 [on 21q22, 7% cases]), transcription regulation (RUNX1 [on 21q22, 9% cases], TP53 [on 17q13, 8% cases], ETV6 [on 12p13, 3% cases], BCOR, PHF6, NCOR, CEBPA, GATA2), tyrosine kinase receptor signaling (JAK2 [on 9p24, 3% cases], MPL, FLT3, GNAS, KIT]), RAS pathways (KRAS, NRAS [on Ip13, 4% cases], CBL [on 11q23, 2% cases], NF1, PTPN11), DNA repair (ATM, BRCC3, DLRE1C, FANCL), and cohesion complexes (STAG2, CTCF, SMC1A, RAD21); and immunologic aberrations (e.g., aberrant immune attack on myeloid progenitors resulting in increased apoptosis) [4–7].
Acute Myeloid Leukemia An Introduction
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
Cytogenetically, normal AML represents 40%–50% of AML patients and often shows genetic abnormalities by molecular testing. The majority of patients with AML developing after MDS [or chronic myelomonocytic leukemia (CMML)] and normal karyotype have mutations in at least one of the ASXL1, TET2, IDH1, or IDH2 genes. They include ITD or mutations of the tyrosine kinase domain (TKD) of the FLT3 gene, Wilms’ tumor 1 gene (WT1) mutations, mutations of the NPM1 gene, partial tandem duplication (PTD) of the MLL gene (MLL-PTD), high expression of the BAALC gene, FIP1L1–PDGFRA fusion, mutations in the CEBPA gene, and abnormalities involving ERG, MN1, and RAS genes [7,13,14,49–56]. More recently discovered abnormalities include mutations in TET2, ASXL1, IDH1 or IDH2, DNA methyltransferase (DNMT)3A, and PHF6. FLT3 and MLL-PTD have been associated with short relapse-free and overall survival, whereas a more favorable outcome is associated with cytogenetically normal cases of AML with mutations in CEBPA or NPM1 (without concomitant FLT3-ITD). In addition, PHF6 and ASXL1 mutations are associated with reduced overall survival, whereas IDH2 mutations are associated with improved overall survival [14]. KIT mutations are associated with reduced overall survival among patients who are positive for t(8;21) corebinding factor alteration but not among the inv(16)/t(16;16) alteration. FLT3 and DNMT3A mutations are significantly associated with NPM1 mutations, whereas ASXL1 mutations have significantly lower incidence of NPM1 and DNMT3A mutations. AML with IDH1 or IDH2 mutations often also have TET2 mutation.
Distinctive phenotypes in two children with novel germline RUNX1 mutations - one with myeloid malignancy and increased fetal hemoglobin
Published in Pediatric Hematology and Oncology, 2020
Shruti Bagla, Katherine A. Regling, Erin N. Wakeling, Manisha Gadgeel, Steven Buck, Ahmar U. Zaidi, Leigh A. Flore, Michael Chicka, Charles A. Schiffer, Meera B. Chitlur, Yaddanapudi Ravindranath
SH2B3 variants have been observed in erythrocytosis not linked to JAK2-V617 mutations and SH2B3 is now recognized as JAK2 activator.30 About 7% of JMML patients harbor SH2B3 mutations, either germline or somatic.55PHF6 encodes a member of nucleosome remodeling and deacetylase complex, with somatic mutations occurring in AML, MDS, CMML, T-cell ALL, Philadelphia chromosome positive chronic myelogenous leukemia (CML) and various other tumors.59–61 Hypofunctioning mutations of PHF6 lead to increased hematopoietic progenitor cells (HPCs) with reduction in the pool of hematopoietic stem cells (HSCs).62 Thus, the hypofunctioning PHF6 variant may have worked cooperatively with the CUX1 and SH2B3 mutation and contributed to the aberrant erythroid proliferation seen in our patient.
The genomic and biological complexity of mixed phenotype acute leukemia
Published in Critical Reviews in Clinical Laboratory Sciences, 2021
Claire Andrews, Anne Tierens, Mark Minden
In the past 18 months, several authors have identified mutations occurring in MPAL and assessed the potential of employing those changes as prognostic factors and therapeutic targets (Table 3) [4–6]. The two largest adult studies, from Takahashi et al. at the MD Anderson Cancer Center (n = 31) [5] and Xiao et al. from the Memorial Sloan Kettering Cancer Center (n = 26), had generally similar results [6]. Both groups found that MPAL cases shared mutations typically found in AML or ALL, although of note there were no NPM1 mutations. The implication of this is that mutation of NPM1 per se does not lead to myeloid/lymphoid lineage aberrancy or that it transforms a cell type that is no longer capable of such differentiation. As the mutations were identified using different panels and methods and the number of cases in both studies was relatively small, as expected, there were some differences in the results of the two studies. For example, the study of Xiao et al. found mutations of PHF6 in 6 of their 31 patients [6], while no patient in the study of Takahashi et al. had this abnormality [5]. Despite this, a number of common themes emerged from the two studies. First, cases with either a BCR-ABL or a KMT2A translocation tended not to have other mutations. Second, MPAL cases tended to have a similar number of mutations as AML, with the median number being 2 versus 3 respectively. The median number of mutations in T-MPAL was 2, while T-ALL had a median of 3 mutations. In contrast, B-MPAL had a median of 2 mutations, while B-ALL had no mutations for the tested genes. A caveat of this is that the mutation analysis was targeted to known AML associated mutations and not to those exclusive to ALL [5].