SÃO VÁRIAS AS MUTAÇÕES DESCRITAS NAS

FALÊNCIAS MEDULARES: DEVEMOS USA-LAS NA

INDICAÇÃO DO TRANSPLANTE?

Rodrigo T. Calado

Divisão de Hematologia, Departamento de Clínica Médica

Faculdade de Medicina de Ribeirão Preto

Universidade de São Paulo

PROCESSO IMUNE

MICROAMBIENTE

CLONALIDADE

CELULARIDADE DA MO

Calado, Seminars in Oncology 2011

DEFININDO A SÍNDROME MIELODISPLÁSTICA

NUMÉRICO

Citopenias

MORFOLÓGICO

Displasia na MO

CLONALIDADE

de blastos

Sideroblastos em anel

Cariótipo anormal

CENÁRIO DE MUTAÇÕES SOMÁTICAS (ADQUIRIDAS) NA SMD

2005:

TP53NRASKRASRUNX1ATRX

2011:

TP53TET2ASXL1RUNX1NRAS/KRASBRAFCBLJAK2EZH2IDH1/IDH2ETV6NPM1

Look. ASH Educ Prog. 2005Bejar et al. NEJM 2011

CENÁRIO DE MUTAÇÕES SOMÁTICAS (ADQUIRIDAS) NA SMD2014

Bejar et al. Blood 2014

PROCESSO IMUNE

MICROAMBIENTE

CLONALIDADE

CELULARIDADE DA MO

Calado, Seminars in Oncology 2011

DNMT3ARUNX1NPM1

JAK2SRSF2ASXL1

CBL

DNMT3ABCORBCOLASXL1

SF3B1SRSF2

CENÁRIO DE MUTAÇÕES SOMÁTICAS (ADQUIRIDAS) NA SMD

Haferlach et al. Leukemia 2014

MUTAÇÕES SOMÁTICAS NO GENE SF3B1 NO BRASIL

7% of MDS cases, all with ring sideroblasts

Donaires et al. RBHH 2016

Genovese et al. NEJM 2014

MUTAÇÕES SOMÁTICAS “DRIVER” EM INDIVÍDUOS SAUDÁVEIS

CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL

Jaiswal et al. NEJM 2014

MUTAÇÕES SOMÁTICAS “DRIVER” AUMENTAM COM A IDADE

CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL

MUTAÇÕES SOMÁTICAS “DRIVER” E O RISCO DE NEOPLASIA HEMATOLÓGICA

CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL

Jaiswal et al. NEJM 2014

CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL

Genovese et al. NEJM 2014

EXPANSÃO CLONAL E FRAÇÃO ALÉLICA

HEMATOPOESE CLONAL

Cooper & Young, Blood, 2017

HEMATOPOESE CLONAL: Normal vs Malignant

Young, Nat Comm, 2016

HEMATOPOESE CLONALNormal versus malignant

Jaiswal, NEJM 2014Genovese, NEJM 2014

American study:3,342 individuals

16 developed hematologic cancer5 carried a candidate gene mutation

2 developed MDS/AML

Swedish study:12,000 individuals

37 developed hematologic cancer10 carried a candidate gene mutation

5 developed MDS/AML

ESPECTRO DE DOENÇAS DOS TELÔMEROSAnemia Aplástica, SMD hereditárias

Bone marrowDyskeratosis congenita (DC)

Aplastic anemia (AA)MDS/HypoMDS

LungIdiopathic pulmonary

fibrosis

LiverCirrhosis

Townsley DM, Blood 2014

MUTAÇÕES SOMÁTICAS NO PROMOTOR DO GENE TERT (TERTp)

Heidenreich & Kumara, 2017

MUTAÇÕES TERTp AUMENTA EXPRESSÃO DE TERT E SE ASSOCIA A TRANSFORMAÇÃO MALIGNA

Heidenreich & Kumara, 2017

TERTp MUTATIONS ARE A MARKER FOR TELOMEROPATHIES

Gutierrez-Rodrigues, submitted

0 0 .5 1 2 4

0

5

1 0

1 5

2 0

2 5

4 0

4 5

5 0

5 5

6 0

Y e a r s

VA

F%

(c

lon

e s

ize

)

-124

-124

-124

-146

-124

A B

0-1

7

18-4

0

41-6

0

61-8

0

0

5

1 0

1 5

2 0

2 5

3 0

Fre

qu

en

cy

of

TE

RT

pm

uta

tio

ns

(%

)

Age range

C

0 1 0 2 0 3 0 4 0 5 0

C D 3 +

C D 1 4 +

T o ta l m o n o n u c le a r

c e lls

M o n o n u c le a r

C D 3 - C D 1 4 -

G ra n u lo c y te s

L e u k o c y te s

m tT E R T p V A F %

N IH 4 6 m u tT E R T p -1 2 4

Gutierrez-Rodrigues, submitted

TelomeropathiesFamily

membersControl group+

DC AA

IPF (with or without AA, MDS, and cirrhosis)

Other phenotyp

es AML

Acquired AA, IPF or other

IBMFS

# with TERTp mutation 2 4 6 0 5 0 0

Total number of patients 21 86 18 11 52 106 89

% of total patients with TERTp 9.5 4.6 33 0 9.6 0 0

# with a germline TERT variant 3 37 14 5 34 0 0

# patients with a somatic TERTp and a germline TERT

mutation0 3 5 0 5 0 0

% patients with a TERTp from the total of patients with TERT

germline mutations0 8.1 36 0 14.7 0 0

TERTp MUTATIONS ARE A MARKER FOR TELOMEROPATHIES

Danazol • Unknown if the presence of TERTp can be translated in better blood counts.

• TERTp clone persists over time

• TERTp clone size may be modulated by Danazol treatment.

• The mechanism of TERT activation is different between somatic promoter mutation and Danazol.

• TERTp and Danazol do not seem to cooperate to restore hematopoiesis

Gutierrez-Rodrigues, unpublished

TERTp CLONE SIZE IS MODULATED BY DANAZOL THERAPY

LANDSCAPE OF SOMATIC VARIANTS IN MARROW FAILURE

Gutierrez-Rodrigues, unpublished

HEMATOPOESE CLONAL

Cooper & Young, Blood, 2017

Danielle Townsley

Thomas Winkler

Neal Young

Régis de Latour

Gérard Socié

Diego Clé

Barbara Santana

Fernanda Rodriguez

Flavia Donaires

André Pinto

Florencia Tellechea

João Paulo Silva

Lilian Figueiredo

Pedro Prata

Guilherme Darrigo

Elvis Valera

Elvira Veloso

Eduardo Rego

Phillip Scheinberg

Carmem Bonfim

Larissa Medeiros

Michel Oliveira