In the winter of 1812, a series of San Andreas earthquakes struck southern California, destroying the original church at San Juan Capistrano and damaging several other 'Las Californias' missions. There were also tsunamis, which would have made coastal living less appealing./2 
After the earthquakes, a number of people living near the 9th Franciscan mission, "San Buenaventura", in present-day Ventura, California, withdrew from the immediate coast & temporarily moved inland to higher ground in another part of what is now Ventura County #VenturaCounty./3
The Mission refugees build small but sturdy earthquake-proof dwellings, similar to those they saw used by the indigenous #Chumash people, which they called “little houses” – the diminutive term for "casa" (house) is “casitas” in Spanish. /4
The mission population returned to Mission San Buenaventura in March 1813. But to quote local Ojai Valley historian Richard Hoye, “The name casitas remained after the people left. It was applied to the Casitas Narrows and Casitas Springs..."/5
"[Casitas] was also used to designate the area extending about a mile to the north of the narrows, which became known simply as The Casitas.” /6 ojaivalleymuseum.org
In the late 1950s, an earthen dam was built across Coyote Creek in that area; it became known as Casitas Dam. Lake Casitas formed in 1959 and completely filled by the 1970s; it provides drinking water to residents of Ventura County (so it is illegal to swim in it). /7
When the Summer Olympic Games were held in Los Angeles in 1984, rowing and sailing events took place on Lake Casitas. (Hopefully no one fell in and contaminated the water.) This is a contemporary postcard./8 #LosAngelesOlympics
In the late 1960s, the heyday of the “viruses cause cancer” concept, scientist Murray Gardner and his colleagues in the Virus Cancer Program @KeckMedUSC were working on oncogenic retroviruses of wild mice and domestic cats. /9 He later went to @ucdavis:
ccm.ucdavis.edu/people/murray-…
ccm.ucdavis.edu/people/murray-…
One colony of feral mice that Gardner and colleagues caught on a farm near Lake Casitas – a brown mouse colony called "Cas-Br-M" – curiously seemed immune to pathological murine leukemia viruses./10
sciencedirect.com/science/articl…
sciencedirect.com/science/articl…
The first virus that caused leukemia in mice – the Gross murine leukemia virus, the murine equivalent of HTLV-1 – was described in 1951 by Ludwik Gross in New York. (A murine breast cancer virus had been described by Bittner in 1936.)/11
Charlotte Friend in NYC identified a different murine leukemia virus in 1956. She worked w/ “Dusty” Rhoads @MSKCC_OncoNotes of "refractory anemia" fame. In 1967, a mouse virus resistance locus was named Fv-1 (Friend virus); the corresponding locus in Casitas mice became Fv-4./12
The Fv-4 defective endogenous murine leukemia virus sequence expressed by resistant mice creates an endogenous retrovirus, which produces an envelope glycoprotein that protects against the exogenous pathogenic virus by binding to the same cell surface receptor, blocking it./13
Most wild mice in North America originated in Europe (in a future tweetorial, I hope to explore the origin of inborn mouse strains via the story of Abbie Lathrop & the Granby Mice.) #LakeCasitas mice, in contrast, originated from China. This map is from the book “Viral Sex.” /14
Lake Casitas mice are thought to have come to North America on ships as part of the so-called “coolie” trade, in which captives were taken from China and India for slave labor in the western US. These hard workers built the trans-continental railroad in the mid-19th century. /15
In 1989, Langdon and colleagues studied the Cas NS-1 murine retrovirus, which causes B-cell lymphomas, and linked it to an oncogene which they called “Casitas B-cell lymphoma”, v-Cbl. Nota bene: they insisted it be pronounced like “Sybil”, not "See-Bee-Ell."/16
Mammalian Cbl genes encode a family of proteins (Cbl, Cbl-b, Cbl-c) that are all protein tyrosine kinase-associated E3 ubiquitin ligases (different from the one that #lenalidomide modulates), which target tyrosine kinases important for hematopoiesis. (Image: Kang B et al SCI)/17
In 2007, two groups - Sargin and colleagues in Münster and Mike Caligiuri and colleagues @OhioStateMed) - simultaneously identified recurrent missense mutations or small in frame deletions in CBL in #AML patient samples. This image is from the Ohio State @BloodJournal paper./18
These somatic mutations abrogate the regulatory E3 ubiquitin ligase activity of CBL. Mutant CBL is thus unable to regulate kinases such as MAPK, FLT3, or MPL and can't appropriately attenuate their signaling. The molecular “brake” is lost./19
As @mrinal90151372 and others have shown, CBL mutations are over-represented in MDS/MPN overlap neoplasms, possibly because of the critical importance of Ras/Raf/MAPK signaling in those disorders. This image is from the GFM, showing CBL mutations in ~12% of CMML./20 #MDS #CMML
No one knows how to target #CBL... yet... maybe someday. And - that's a wrap for tonight. Hope you enjoy these tweetorials! They take quite a while to make, so I'm going to take a break for a while, but it is fun for me to assemble all of these various strands./21End #Blackjack
