Key Points Proinflammatory MKs from mice with GPS drive the extension of myelofibrosis, splenomegaly, and emperipolesis. The lack of preformed α-granules in Nbeal2−/− platelets leads to protection against cancer metastasis.

Somatic mutations in the endoplasmic reticulum chaperone calreticulin (CALR) are detected in approximately 40% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). Multiple different mutations have been reported, but all result in a +1-bp frameshift and generate a novel protein C terminus. In this study, we generated a conditional mouse knockin model of the most common CALR mutation, a 52-bp deletion. The mutant novel human C-terminal sequence is integrated into the otherwise intact mouse CALR gene and results in mutant CALR expression under the control of the endogenous mouse locus. CALR mice develop a transplantable ET-like disease with marked thrombocytosis, which is associated with increased and morphologically abnormal megakaryocytes and increased numbers of phenotypically defined hematopoietic stem cells (HSCs). Homozygous CALR mice developed extreme thrombocytosis accompanied by features of MF, including leukocytosis, reduced hematocrit, splenomegaly, and increased bone marrow reticulin. CALR HSCs were more proliferative in vitro, but neither CALR nor CALR displayed a competitive transplantation advantage in primary or secondary recipient mice. These results demonstrate the consequences of heterozygous and homozygous CALR mutations and provide a powerful model for dissecting the pathogenesis of CALR-mutant ET and PMF.

In Experiments 1 and 2, rats were exposed to two compound flavors, AXand BX, containing one flavor in common (X). Following this exposure phase, an aversion was conditioned to A in the experimental group by pairing its consumption with an injection of lithium, while a control group drank A without being poisoned. The effect of this treatment was to establish B as a conditioned inhibitor. In Experiment 1, experimental animals were slower than controls to condition an aversion to B when its consumption was paired with lithium (a retardation test of conditioned inhibition). In Experiment 2, B alleviated the suppression of intake of another flavor previously paired with lithium (a summation test). Experiments 3 and 4 established that these effects depended upon prolonged prior exposure to AX and BX.In their theory of stimulus representation, McLaren, Kaye, and Mackintosh (1989) suggested that exposure to two compound stimuli (AX and BX), containing a common element X, would permit the establishment of two types of associations between the elements of each compound. The first would be excitatory associations between the common element X and each unique element, A and B. The existence of such associations is evident from studies such as that of Rescorla and Cunningham (1978), employing compound flavors. Their effect will presumably be to enhance generalization between the two compounds: if AX is paired with an unconditioned stimulus (US), the ability of X to retrieve a representation of B could result in excitatory conditioning to B as well as to A on this trial. Acquired equivalence effects of this sort have been demonstrated by Hall (1989, 1991).It is well established, however, that prolonged exposure to AX and BX will often facilitate subsequent discrimination, rather than increase generalization between them (Hall, 1991). McLaren et al. (1989) attribute this perceptual learning etTect, in part, to differences in the associability of the common (X) and unique (A and B) elements, which occur as a consequence of greater latent inhibition of the former than of the latter. Several studies have provided good evidence for such a suggestion (e.g., Mackintosh, Kaye, & Bennett, 1991; Rodrigo, Chamizo, McLaren, & Mackintosh, 1994) see Experiments 3 and 4) concluded that such differential latent inhibition of common and unique elements could not be the only explanation of perceptual learning. They suggested that one additional mechanism was provided by a second set of associations that are formed between the elements of AX and BX-~specifically, inhibitory associations between A and 8. The establishment of excitatory associations between common and unique elements may cause X to retrieve a representation of B on AX trials (and of A on BX trials), but the presence of A signals the absence of the otherwise expected B (just as the presence of B signals the absence of the otherwise expected A), and according to standard associative theory, this should lead to the eventual establishment of inhibitory associations between A and B...