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- Isobe, T, et al.
(författare)
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Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia
- 2022
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 4501-
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Tidskriftsartikel (refereegranskat)abstract
- KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) represents the most refractory type of childhood leukemia. To uncover the molecular heterogeneity of this disease, we perform RNA sequencing, methylation array analysis, whole exome and targeted deep sequencing on 84 infants with KMT2A-rearranged leukemia. Our multi-omics clustering followed by single-sample and single-cell inference of hematopoietic differentiation establishes five robust integrative clusters (ICs) with different master transcription factors, fusion partners and corresponding stages of B-lymphopoietic and early hemato-endothelial development: IRX-type differentiated (IC1), IRX-type undifferentiated (IC2), HOXA-type MLLT1 (IC3), HOXA-type MLLT3 (IC4), and HOXA-type AFF1 (IC5). Importantly, our deep mutational analysis reveals that the number of RAS pathway mutations predicts prognosis and that the most refractory subgroup of IC2 possesses 100% frequency and the heaviest burden of RAS pathway mutations. Our findings highlight the previously under-appreciated intra- and inter-patient heterogeneity of KMT2A-rearranged infant ALL and provide a rationale for the future development of genomics-guided risk stratification and individualized therapy.
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- Ochi, Y, et al.
(författare)
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Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia
- 2021
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 2833-
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Tidskriftsartikel (refereegranskat)abstract
- Blast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML.
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- Aharonian, Felix, et al.
(författare)
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Hitomi X-ray studies of giant radio pulses from the Crab pulsar
- 2018
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Ingår i: Publications of the Astronomical Society of Japan. - : Oxford University Press (OUP). - 0004-6264 .- 2053-051X. ; 70:2
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Tidskriftsartikel (refereegranskat)abstract
- To search for giant X-ray pulses correlated with the giant radio pulses (GRPs) from the Crab pulsar, we performed a simultaneous observation of the Crab pulsar with the X-ray satellite Hitomi in the 2-300 keV band and the Kashima NICT radio telescope in the 1.4-1.7 GHz band with a net exposure of about 2 ks on 2016 March 25, just before the loss of the Hitomi mission. The timing performance of the Hitomi instruments was confirmed to meet the timing requirement and about 1000 and 100 GRPs were simultaneously observed at the main pulse and inter-pulse phases, respectively, and we found no apparent correlation between the giant radio pulses and the X-ray emission in either the main pulse or inter-pulse phase. All variations are within the 2 sigma fluctuations of the X-ray fluxes at the pulse peaks, and the 3 sigma upper limits of variations of main pulse or inter-pulse GRPs are 22% or 80% of the peak flux in a 0.20 phase width, respectively, in the 2-300 keV band. The values for main pulse or inter-pulse GRPs become 25% or 110%, respectively, when the phase width is restricted to the 0.03 phase. Among the upper limits from the Hitomi satellite, those in the 4.5-10 keV and 70-300 keV bands are obtained for the first time, and those in other bands are consistent with previous reports. Numerically, the upper limits of the main pulse and inter-pulse GRPs in the 0.20 phase width are about (2.4 and 9.3) x 10(-11) erg cm(-2), respectively. No significant variability in pulse profiles implies that the GRPs originated from a local place within the magneto-sphere. Although the number of photon-emitting particles should temporarily increase to account for the brightening of the radio emission, the results do not statistically rule out variations correlated with the GRPs, because the possible X-ray enhancement may appear due to a > 0.02% brightening of the pulse-peak flux under such conditions.
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