While the NF1 and TP53 TSGs follow the Knudson two-hit paradigm and undergo biallelic inactivation, there is increasing evidence that inactivation of a single allele of TSG such as RUNX1, PU.1 and RPS14 (haploinsufficiency) can also contribute to leukemogenesis.
The two-hit paradigm of tumour suppressor gene mutation has held sway for many years.
However, novel concepts in tumour suppressor genetics such as haploinsufficiency currently challenge the two-hit paradigm and are gaining importance in cancer genetics.
The current "two-hit" paradigm in cancer biology, similarly, shows that early-life insult can predispose the individual to disease development in response to a second hit of an environmental exposure or even an endogenous hormone.
In broadest terms, single-copy loss of a suppressor gene can be sufficient to modify gene function and promote tumorigenesis (classical haploinsufficiency), while in other tumors, the loss of two alleles is required (two-hit paradigm of Knudson) (Knudson, 1971).
Contrary to the original 2-hit paradigm for tumour suppressor genes, where both alleles must be inactivated to elicit a growth promoting phenotype, ample evidence from in vivo and in vitro studies and human tumour analyses demonstrates that not only the absence, but also the moderate reduction of tumour suppressor gene products can be sufficient to alter growth phenotype.
The fact is, even though we'll always have our share of ultra-hyped iPhones, the biggest hits and paradigm-shifters are often complete surprises.
Recently an extremely low volume high-intensity interval training paradigm (HIT), consisting of no more than 7.5 minutes of exercise per week, has been proposed as a novel, time-efficient exercise regime for improving aerobic fitness [ 4, 14].
Cas9 expression was transient in neonates, representing an attractive "hit-and-run" paradigm.
Paul Ehrlich's paradigm to "hit early and hard" in treatment of infectious disease [44] to limit spread of an infectious pathogen and to contain its population size, toxicity, and its potential to escape immunological and chemotherapeutic/medical control [45] is still valid and accepted.
