sÃo vÁrias as mutaÇÕes descritas nas falÊncias...
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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