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Sotos Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
It should be noted that mutation in the nuclear factor I/X type gene (NFIX) on chromosome 19p13.3 may produce an autosomal dominant disorder known as Malan syndrome (or Sotos syndrome 2) [11–13]. Nuclear factor I is a ubiquitous 47-kD dimeric DNA-binding protein with the capability of stimulating the transcription of genes in cooperation with other factors such as estrogen receptor (ESR). In addition, alteration in the APC2 gene on chromosome 19p13.3 may cause an autosomal recessive disease known as Sotos syndrome 3. APC2 is a 2303-aa protein gene preferentially expressed in postmitotic neurons. As NSD1 is shown to downregulate APC2 in neurons, it is no surprise that Apc2-deficient (Apc2−/−) mice exhibit impaired learning and memory abilities along with an abnormal head shape [14,15]. Given that the mitogen-activated protein kinase (MAPK) pathway is a diminished activity state in Sotos syndrome, it may be also involved in statural overgrowth and accelerated skeletal maturation [16]. In addition, NSD1 forms as a fusion transcript with NUP98, playing a part in leukemogenesis through H3K36 methylation and subsequent HOX-A gene activation, particularly childhood acute myeloid leukemia [17].
Resistance to Imatinib
Published in Jorge Cortes, Michael Deininger, Chronic Myeloid Leukemia, 2006
Duyster Justus, Bubnoff Nikolas von
In a small subset of imatinib resistant patients, it can be shown that the drug still effectively blocks BCR-ABL kinase activity. This indicates that the leukemia has become at least partially BCR-ABL independent as a result of secondary genetic events. Clonal cytogenetic evolution is frequently associated with imatinib resistance (7,40,41) and has been demonstrated to be an independent poor prognostic factor for survival in CML (42). However, the molecular mechanisms by which specific chromosomal alterations lead to resistance are not understood. Two frequently described cytogenetic abnormalities are isochromosome 17, leading to inactivation of p53 (43,44), and trisomy 8, resulting in amplification and overexpression of MYC (45). Both events may contribute to disease progression and imatinib resistance (45–47). In one imatinib-resistant CML patient, an inversion of chromosome 11 [inv(11)(p15q22)] led to the expression of a NUP98/DDX10 fusion protein (48). Interestingly, NUP98/DDX10 is also associated with AML and myelodysplastic syndromes and, thus, may play a functional important role for disease progression and imatinib resistance (49).
Addition of venetoclax to myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in high-risk AML
Published in Annals of Medicine, 2023
Xing-yu Cao, Jia-qi Chen, Hui Wang, Wei Ma, Wei-wei Liu, Fang-fang Zhang, Song Xue, Lei Dong, Ting Liu, Xiao-zhen Zhao, Chan-chan Liu, Xin Xu, Yang He, Lei Wang, Jian-ling Wang
NUP98::rearranged AML are now recognized as a high-risk subtype of leukemia [36], and NUP98-NSD1 was found in 15% of FLT3/ITD and 7% of cytogenetically normal (CN)-AML. Those with dual FLT3/ITD and NUP98::NSD1 (82% of NUP98::NSD1 positive patients) had a CR rate of 27 vs. 69% among those patients with FLT3/ITD but without the NUP98::NSD1 fusion (p < 0.001). The corresponding 3-year OS was 31 vs. 48% (p = 0.011), respectively [37]. NUP98::HOXA9 fusion AML had a median OS of 13.5 months [38]. In our study, 4 patients were positive for the NUP98::SD1 fusion gene and 1 patient was positive for the NUP98::HOXA9 fusion gene. Two patients were refractory to chemotherapy and 3 patients were MRD-positive prior to transplantation. During the follow-up, all patients remained alive. Median OS was significantly shorter for AML patients harboring MLL-PTD and FLT3-ITD mutations [39]. The MLL(KMT2A) rearrangement was associated with adverse prognosis regardless of translocation subtype [40]. Allo-HSCT in CR1 was associated with improved OS (52% at 5 years vs 14% for those without allo-HSCT, p < 0.0001) [40]. The 5-year OS was 42% and the 5-year RI was 37% (n = 426) for patients with the MLL rearrangement post-HSCT in the CIBMTR database [41]. The 1-year OS for the 7 patients (2 patients in NR before transplantation) with the MLL rearrangement or MLL-PTD was 83.3% (95% CI, 46.5–100%). These results suggest that the MAC regimen containing venetoclax is particularly effective for AML patients with NUP98 rearranged or MLL-PTD disease.
Acute myeloid leukemia with NUP98::RARG resembling acute promyelocytic leukemia accompanying ARID1B gene mutation
Published in Hematology, 2023
Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) characterized by fatal coagulation abnormalities. More than 98% of patients with APL have a promyelocytic leukemia–retinoic acid receptor alpha (PML::RARA) fusion gene caused by the chromosomal translocation t (15; 17) (q22; q21), which is sensitive to therapy with ATRA and arsenic trioxide (ATO) therapy[1,2]. However, certain AML subtypes exhibit the APL phenotype and APL-like syndromes, with X::RARs fusion genes rather than the PML–RARA fusion gene [2]. In the past few years, X::RARA has been well described, including PLZF::RARA, NPM1::RARA, and STAT5B::RARA. Furthermore, retinoic acid receptor beta(RARB) and retinoic acid receptor gamma(RARG) rearrangements have been discovered to contribute to APL-like syndromes [3]. Notably, RARB and RARG share high sequence homology with RARA[4], and unlike PML::RARA fusions, most novel X::RAR fusions are ATRA or ATO resistant. In this study, we report the case of a patient with AML with a NUP98::RARG rearrangement and review our current understanding of patients with AML harboring X::RAR fusion gene.
Hyperleukocytosis predicts inferior clinical outcome in pediatric acute myeloid leukemia
Published in Hematology, 2020
Lu-Hong Xu, Jing-Wen Wang, Yin Wang, Feng-Ying Yang
As shown in Figure S2, NUP98-NSD1 gene fusion conferred poor clinical outcomes in AML patients in term of 5-year EFS (P < 0.001) and OS (P = 0.029). The survival curves of pediatric AML patients according to the combined HL and NUP98-NSD1 status are shown in Figure 3. When restricted to no NUP98-NSD1 group, HL was correlated with worse 5-year EFS (40.6 ± 4.6% HL vs 51.8 ± 2.6% non-HL, P = 0.018) but not 5-year OS (60.3 ± 4.7% HL vs 68.2 ± 2.4% non-HL, P = 0.142). However, when restricted to NUP98-NSD1 group, HL showed both significantly worse 5-year EFS (11.8 ± 7.8% HL vs 40.3 ± 12.1% non-HL, P = 0.004) and OS (22.1 ± 10.9% HL vs 75.5 ± 10.7% non-HL, P = 0.002).