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Somatic mutations in TP53 and NRAS are associated with transformation of human chronic myeloid diseases to acute myeloid leukemia (AML). Here, we report that concurrent RAS pathway and TP53 mutations are identified in a subset of AML patients and confer an inferior overall survival. To further investigate the genetic interaction between p53 loss and endogenous Nras in AML, we generated conditional Nrasp53 mice. Consistent with the clinical data, recipient mice transplanted with Nrasp53 bone marrow cells rapidly develop a highly penetrant AML. We find that p53 cooperates with Nras to promote increased quiescence in megakaryocyte-erythroid progenitors (MEPs). Nrasp53 MEPs are transformed to self-renewing AML-initiating cells and are capable of inducing AML in serially transplanted recipients. RNA sequencing analysis revealed that transformed MEPs gain a partial hematopoietic stem cell signature and largely retain an MEP signature. Their distinct transcriptomes suggests a potential regulation by p53 loss. In addition, we show that during AML development, transformed MEPs acquire overexpression of oncogenic Nras, leading to hyperactivation of ERK1/2 signaling. Our results demonstrate that p53 synergizes with enhanced oncogenic Nras signaling to transform MEPs and drive AML development. This model may serve as a platform to test candidate therapeutics in this aggressive subset of AML.

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A small-diameter polarization-maintaining photonic crystal fiber (PM-PCF) for mini coils of spaceborne miniature fiber-optic gyroscopes is proposed in this paper. To ensure the strength of the small-diameter PM-PCF, a four-ring air holes structure is adopted. Using the full vector finite element method, dependence studies of modal field distribution, birefringence, and confinement loss on several key structure parameters are numerically investigated. The optimized parameter region is obtained. An optimized PM-PCF is fabricated, which can achieve similar to or even better optical properties than that of commercial PM-PCFs. The coating and cladding diameters of the optimized PM-PCF are 135 μm and 100 μm, respectively. Meanwhile, the optimized small-diameter PM-PCF shows a proof test level of 0.5%. The attenuation of the PM-PCF at 1550 nm is ∼2  dB/km. Typical volume of a mini coil wound with 300 m optimized PM-PCF is 5.9  cm3, which is decreased by ∼60% compared with a commercial PM-PCF coil of the same length. The bias stability of this coil is comparable with that of a conventional PMF coil of comparable length. Thus, the optimized small-diameter PM-PCF is suitable for mini coils of spaceborne miniature fiber-optic gyroscopes.

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