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Patients with acute myeloid leukaemia (AML)

and hairy cell leukaemia (HCL) are more likely

to receive appropriate, effective treatments

today than they were a decade ago, thanks

to important advances in our understanding

of the conditions at a molecular level. The

identification of some of the key genetic

variations underlying different forms of these

blood cancers have allowed better targeting of

existing therapies and provided the foundations

for the development of new treatments.

Brunangelo Falini is widely recognized

as having led this scientific charge. On 6

May 2015 he received the prestigious French

ARC Foundations Leopold Griffuel Award

for translational and clinical research at

a ceremony in Paris in recognition of his

achievements. Here, he reveals what has driven

his quest to better understand and treat these

diseases, and explains how caring for patients

inspires his research and vice versa.

Q: Could you describe your key

breakthrough in AML research?

About 15 years ago we observed that in

about 30% of AML cases, a protein called

nucleophosmin (NPM1) appeared not to be

expressed in the cell nucleus as we expected

but, surprisingly in the cytoplasm . ese were

AML with normal cytogenetics patients - those

in which you could not nd abnormalities

with cytogenetic techniques for examining

chromosomes. is was before the widespread

availability of whole genome sequencing,

however we were able to sequence single genes,

and therefore were able to identify the mutation

in the NPM1 gene responsible for causing

this type of AML. In 2008 the World Health

Organisation recognized NPM1-mutated AML as

a new form of leukaemia.

Q: How has this advance helped

these patients?

AML patients are treated based on clinical

parameters, but especially according to

molecular alterations of leukaemia cells. We now

know that having the NPM1 mutation can give

patients a more favourable prognosis depending

on what versions of another gene they have. e

denition of NPM1-mutated AML as a separate

condition and understanding the eects of

dierent gene variant combinations can help

doctors determine whether the best treatment

is chemotherapy on its own or transplantation

of stem cells that generate healthy blood cells,

which can cure those with poor prognosis but

carries a high mortality risk.

Q: What was your major contribution to

HCL research?

Although it had long been possible to

recognize the unusual shape of HCL cells

under the microscope, their underlying genetic

characteristics remained a mystery for over

half a century. In 2011 we used whole exome

sequencing to nd ve genetic mutations present

in a patients HCL cells but not in their healthy

ones. Among them was a BRAF mutation that

was already implicated in melanomas and

we found it to be present in all 48 HCL cases

checked. Later validation points to it being the

disease-dening genetic lesion of HCL.

Patients with HCL can usually be diagnosed

under the microscope, but there are other

leukaemias and lymphomas that resemble it.

We found that the BRAF mutation is, with rare

exceptions, specic to HCL among lymphomas,

so in 2012 we developed the rst molecular test

for the condition. ats important because

there are drugs called purine analogues that

are quite eective for HCL, but not for other

blood cancers that can mimic it. Last year

we completed a phase II trial using the BRAF

inhibitor Vemurafenib for 28 patients for whom

standard therapies had failed. We had benecial

responses in all but one patient, with complete

remission in about 35% of participants and partial

remission in 61%.

Q: Does research or clinical work give you

the most satisfaction?

For me the two are inseparable. It is not only

about going from the bench to the patient, but

also from the patient to the bench. Because I

have spent time investigating the morphological

features and genetic alterations of lymphomas

and leukaemias, I am better able to categorize

my patients cancers, understand their disease

progression and determine the best therapeutic

strategy. Im also constantly brought face-to-face

with the reality that many patients still succumb

to their leukaemias and lymphomas, and this

provides the strongest possible motivation for

my research and translation eorts. Clinical

observations have led me to investigate specic

things and helped me understand that, in

addition to developing new drugs, we should

also re-think old drugs in the light of the new

genomics knowledge.

Q: What inspired your career choices?

In 1908 my great-grandfather Undecimo

Bindocci, who was a chemist and pharmacist,

won a gold medal at an international exposition

also in Paris for his invention of the eervescent

laxative. I did not meet him but my parents

often talked of his creativity. His medal still

hangs on the wall of the family pharmacy run

by my brother in Perugia. My grandfather was

a veterinarian, and both my grandmother and

father were pharmacists, so science was often

in the air in our family. Another major inuence

was that from adolescence, for reasons I cannot

explain, I was afraid of getting sick and being

destroyed by cancer, while also being extremely

curious about the mysteries underlying the

disease. My curiosity triumphed over my fears

and led me to the fascination that became my

lifes work.

Q: What does winning the Leopold Griuel

Award mean to you and how will you

spend the prize money?

When I look at the list of previous winners I

sometimes feel that I do not deserve it. Its a

real honour. It is also an opportunity because it

comes with 125,000 to promote research. AML

remains an incurable disease in 50% of patients

below the age of 60 and in 85-90% of older

patients, so although nothing has been nalized,

Id like to use this money as part of our eorts to

nd new drugs to treat it better.

Brunangelo Falini, Professor of Haematology, University of Perugia, Italy

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In addition to developing new drugs, we should also re-think old drugs in the light of the new genomics knowledge.

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Leopold

Griffuel

awards

Deadline for nominations

INFORMATION W W W.RECHERCHE-CANCER.NET

The ARC Foundation Leopold Griffuel Awards are one of the most SUHVWLJLRXVVFLHQWLFDZDUGVLQFDQFHUUHVHDUFKLQ(XURSH6LQFH1970, the ARC Foundation honors scientists and physicians who have made major contributions in the understanding, diagnosis, treatment and prevention of cancers. It was established according to Mrs Griffuels will, in honor and memory of her late husband, Mr Leopold Griffuel.

JULY 31sT, 2015

2 Awards of 150,000Basic Research &

Translational and

Clinical Research

rewarding major breakthroughs in

CANCER RESEARCH

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