Publications

BACKGROUND

Many widely used myocardial T1 mapping sequences use breath-hold acquisitions that limit the precision of calculated T1 maps. The SAturation-recovery single-SHot Acquisition (SASHA) sequence has high accuracy with robustness against systematic confounders, but has poorer precision compared to the commonly used MOdified Look-Locker Inversion recovery (MOLLI) sequence. We propose a novel method for generating high-contrast SASHA images to enable a robust image registration approach to free-breathing T1 mapping with high accuracy and precision.

METHODS

High-contrast (HC) images were acquired in addition to primary variable flip angle (VFA) SASHA images by collecting an additional 15 k-space lines and sharing k-space data with the primary image. The number of free-breathing images and their saturation recovery times were optimized through numerical simulations. Accuracy and precision of T1 maps using the proposed SASHA-HC sequence was compared in 10 volunteers at 1.5 T to MOLLI, a breath-hold SASHA-VFA sequence, and free-breathing SASHA-VFA data processed using conventional navigator gating and standard image registration. Free-breathing T1 maps from 15 patients and 10 volunteers were graded by blinded observers for sharpness and artifacts.

RESULTS

Difference images calculated by subtracting HC and primary SASHA images had greater tissue-blood contrast than the primary images alone, with a 3× improvement for 700 ms TS saturation recovery images and a 6× increase in tissue-blood contrast for non-saturated images. Myocardial T1s calculated in volunteers with free-breathing SASHA-HC were similar to standard breath-hold SASHA-VFA (1156.1 ± 28.1 ms vs 1149.4 ± 26.5 ms, p >0.05). The standard deviation of myocardial T1 values using a 108 s free-breathing SASHA-HC (36.2 ± 3.1 ms) was 50 % lower (p <0.01) than breath-hold SASHA-VFA (72.7 ± 8.0 ms) and 34 % lower (p <0.01) than breath-hold MOLLI (54.7 ± 5.9 ms). T1 map quality scores in volunteers were higher with SASHA-HC (4.7 ± 0.3 out of 5) than navigator gating (3.6 ± 0.4, p <0.01) or normal registration (3.7 ± 0.4, p <0.01). SASHA-HC T1 maps had comparable precision to breath-hold MOLLI using a retrospectively down-sampled 30 s free-breathing acquisition and 30 % higher precision with a 60 s acquisition.

CONCLUSIONS

High-contrast SASHA images enable a robust image registration approach to free-breathing T1 mapping. Free-breathing SASHA-HC provides accurate T1 maps with higher precision than MOLLI in acquisitions longer than 30 s.

Homeobox (HOX) proteins and the receptor tyrosine kinase FLT3 are frequently highly expressed and mutated in acute myeloid leukemia (AML). Aberrant HOX expression is found in nearly all AMLs that harbor a mutation in the Nucleophosmin (NPM1) gene, and FLT3 is concomitantly mutated in approximately 60% of these cases. Little is known about how mutant NPM1 (NPM1) cells maintain aberrant gene expression. Here, we demonstrate that the histone modifiers MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1 AML. Using a CRISPR/Cas9 genome editing domain screen, we show NPM1 AML to be exceptionally dependent on the menin binding site in MLL1. Pharmacologic small-molecule inhibition of the menin-MLL1 protein interaction had profound antileukemic activity in human and murine models of NPM1 AML. Combined pharmacologic inhibition of menin-MLL1 and DOT1L resulted in dramatic suppression of HOX and FLT3 expression, induction of differentiation, and superior activity against NPM1 leukemia.

SIGNIFICANCE

MLL1 and DOT1L are chromatin regulators that control HOX, MEIS1, and FLT3 expression and are therapeutic targets in NPM1 AML. Combinatorial small-molecule inhibition has synergistic on-target activity and constitutes a novel therapeutic concept for this common AML subtype. Cancer Discov; 6(10); 1166-81. ©2016 AACR.See related commentary by Hourigan and Aplan, p. 1087This article is highlighted in the In This Issue feature, p. 1069.