Thread by @DavidSteensma

#HematologyTweetstory 9: the “Philadelphia” chromosome! Whole books have been written about this saga; we’ll focus on some of the most interesting highlights. A shout-out to @LuskinMarlise – former @PennMedicine fellow & now @DanaFarber colleague - for suggesting this topic. /1

The key discovery in a "nutshell" (karyo=nut in Greek): in 1959, David Hungerford (1927-1993) and Peter Carey Nowell (1928-2016) @Penn found a peculiar-looking tiny chromosome in cells from 7 patients w/ a disease then called “chronic granulocytic leukemia", now known as #CML./2

Nowell, a Philadelphia native, had graduated from @Penn in 1952 and then returned to join the faculty in 1956 after doing radiobiology research while in the US Navy. He started working on leukemia, not really sure where his research was going, then had a happy accident./3

While rinsing blood cells with hypotonic tap water before staining and mounting them on a microscope slide - he didn't know any better - he inadvertently caused the cells to swell and flatten and also disrupted the mitotic spindle, allowing easier visualization of chromosomes. /4

Recognizing an opportunity, he called around trying to find someone who knew something about chromosomes. At UPenn's Institute for Cancer Research (a @FoxChaseCancer precursor) he found a grad student, David Hungerford - originally from Brockton, Mass. - who was interested./5

Using Nowell’s preparations, Hungerford noticed something strange in "CGL" samples – a tiny chromosome, which was not present in any acute leukemias or in normal cells. I think you'll agree with me that it took a pretty good eye to see this, given karyotype resolution in 1959. /6

Here’s their classic abstract, from a National Academy meeting in Philadelphia, published in @sciencemagazine on 18 Nov. 1960. (I also took a picture of the journal cover; looks different today!) It's been cited thousands of times & was <200 words: "Brevity is the soul of wit."/7

To underscore how surprising this finding was, at the time many people thought cancer was primarily caused by viruses (cf. @DrSidMukherjee book) or emotional repression. #SusanSontag, who died of MDS, wrote about the latter extensively in her 1978 book, “Illness as Metaphor”./8

And karyotyping was in its infancy. Only in 1956 had Joe Hin Tjio (from a Chinese family and born in the Dutch East Indies) & Albert Levan @LundUniversity in Sweden sorted out that humans have 46 chromsomes, not 48 (which was commonly thought at the time) or some other number./9

Most #karyotypes of the era looked something like these. You would lyse colchicine-treated cells, stain with Giemsa or quinacrine, take photographs of the cell spread, then cut chromosomes out of a good photo and line them up and glue them on a sheet of paper. /10

When I rotated in cytogenetics @MayoClinic in the 1990s, the lab was still equipped to do it the cut&paste way and just converting to digital. I hadn’t done so much work with rubber cement and glue sticks since making collages out of construction paper in kindergarten. 😄 /11

As a result, chromosomes were not usually numbered, they were grouped, since it was essentially impossible to tell, say, chromosome 4 from 5. Hungerford & Nowell didn’t know their weird chromosome was a derivative 22. All they could say: “One of the four smallest autosomes.”/12

•Group A (1-3)=large metacentric
•Group B (4-5)=large submetacentric
•Group C (6-12, X)=medium submetacentric (many)
•Group D (13-15)=medium acrocentric
•Group E (16-18)=short submetacentric
•Group F (19-20)=short metacentric
•Group G (21-22, Y)=short acrocentric

But techniques soon improved enough that by 1974, when Herman van den Berghe in Leuven described a recurrent alteration in “preleukemia”, he knew it was chromosome 5 that was missing its long arm... we know this as "del(5q) MDS". (This is from HvdB's obit @bmj_latest)/14

Hungerford & Nowell’s discovery quickly became known as the “Philadelphia” chromosome. It’s always best if someone else names something in your honor – bad practice to name it after yourself. In this case, the name was suggested by an Edinburgh cytogenetics group, so all good./15

A brief aside: as a New Jersey kid, I have always had a a certain affection for gritty Philly. Our first out-of-state class trip included a stop at Wanamaker's to see the Christmas Light Show; this photo of the old light show is attributed to Bruce Andersen via Wikimedia./16

In 1962, a second “city chromosome” was described in @bmj_latest by Fred Gunz et al. Gunz was a remarkable character and brilliant Austrian Jewish exile. They thought they’d solved the genetic basis of #CLL. This chromosome was named after Christchurch in New Zealand./17

Within 4 years, it was clear the "Christchurch chromosome" (4 Ch's!) was not linked to #CLL the way Philadelophia chromosome was associated with #CML. Christchurch was germline, and seen only in a few local Kiwi families. In fact, karyotyping has always been hard in #CLL./18

Janet Davison Rowley (1925-2013) @UChicagoMed , karyotyping pioneer, found the Philadelphia chromosome was a translocation between chromosomes 9 & 22. She was raising 4 children at the time & often cautioned her kids not to sneeze & send chromosomes flying off the kitchen table.

When I was a student at @UChicagoMed many of us deeply admired Dr Rowley. She inspired numerous careers in cancer and genetics, I think especially for women. She followed her 1972 Ph discovery with a 2nd chromosomal translocation in leukemia in 1973, this one in #AML: t(8;21).

On the home stretch now. In 1982, Annelies de Klein and her colleagues @erasmusuni in Rotterdam found the key gene translocated in t(9;22) was "c-abl", homolog of the Abelson leukemia virus, discovered in 1970 by later @UChicagoMed pediatrics chair Herbert T. Abelson./21

In 1984, ABL was found to encode a tyrosine kinase. Then in 1990, @G_Q_Daley - now @harvardmed Dean, but back then working in David Baltimore's lab - and his colleagues definitively showed BCR/ABL was oncogenic by using it to generate leukemia in some (unlucky) mice. 🐁🧬/22

The rest of the story is well known. Brian Druker @OHSUKnight, who for some unexplained reason has not yet won the Nobel Prize, with Ciba-Geigy developed a tyrosine kinase inhibitor called CGP 57148, later known as STI-571 and imatinib, which inhibits ABL & revolutionized CML./23

My first @ASH_hematology annual meeting was #ASH98 in Miami Beach; STI-571 merited a poster. I remember thinking "interesting idea - probably won't work." 🤦‍♂️The following year #ASH99 in New Orleans, amazing clinical data were presented - in a hall that was standing room only./24

The drug name, Glivec or Gleevec, was recycled by @Novartis from a failed glioblastoma drug. If you’re interested in reading more about this cool story, I am told the book by @jessicawapner is excellent - hope to read it myself in the months to come. /25End