Human leukemia mutations corrupt but do not abrogate GATA-2 function

Koichi R. Katsumura, Charu Mehta, Kyle J Hewitt, Alexandra A. Soukup, Isabela Fraga De Andrade, Erik A. Ranheim, Kirby D. Johnson, Emery H. Bresnick

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

By inducing the generation and function of hematopoietic stem and progenitor cells, the master regulator of hematopoiesis GATA- 2 controls the production of all blood cell types. Heterozygous GATA2 mutations cause immunodeficiency, myelodysplastic syndrome, and acute myeloid leukemia. GATA2 disease mutations commonly disrupt amino acid residues that mediate DNA binding or cis-elements within a vital GATA2 intronic enhancer, suggesting a haploinsufficiency mechanism of pathogenesis. Mutations also occur in GATA2 coding regions distinct from the DNA-binding carboxyl-terminal zinc finger (C-finger), including the aminoterminal zinc finger (N-finger), and N-finger function is not established. Whether distinct mutations differentially impact GATA-2 mechanisms is unknown. Here, we demonstrate that N-finger mutations decreased GATA-2 chromatin occupancy and attenuated target gene regulation. We developed a genetic complementation assay to quantify GATA-2 function in myeloid progenitor cells from Gata2 -77 enhancer-mutant mice. GATA-2 complementation increased erythroid and myeloid differentiation. While GATA-2 disease mutants were not competent to induce erythroid differentiation of Lin-Kit + myeloid progenitors, unexpectedly, they promoted myeloid differentiation and proliferation. As the myelopoiesis-promoting activity of GATA-2 mutants exceeded that of GATA-2, GATA2 disease mutations are not strictly inhibitory. Thus, we propose that the haploinsufficiency paradigm does not fully explain GATA-2-linked pathogenesis, and an amalgamation of qualitative and quantitative defects instigated by GATA2 mutations underlies the complex phenotypes of GATA- 2-dependent pathologies.

Original languageEnglish (US)
Pages (from-to)E10109-E10118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number43
DOIs
StatePublished - Oct 23 2018

Fingerprint

Leukemia
Mutation
Fingers
Haploinsufficiency
Zinc Fingers
Hematopoietic Stem Cells
Myelopoiesis
Myeloid Progenitor Cells
DNA
Myelodysplastic Syndromes
Hematopoiesis
Acute Myeloid Leukemia
Chromatin
Blood Cells
Pathology
Phenotype
Amino Acids
Genes

Keywords

  • AML
  • GATA-2
  • Hematopoiesis
  • Leukemia
  • MDS

ASJC Scopus subject areas

  • General

Cite this

Human leukemia mutations corrupt but do not abrogate GATA-2 function. / Katsumura, Koichi R.; Mehta, Charu; Hewitt, Kyle J; Soukup, Alexandra A.; De Andrade, Isabela Fraga; Ranheim, Erik A.; Johnson, Kirby D.; Bresnick, Emery H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 43, 23.10.2018, p. E10109-E10118.

Research output: Contribution to journalArticle

Katsumura, Koichi R. ; Mehta, Charu ; Hewitt, Kyle J ; Soukup, Alexandra A. ; De Andrade, Isabela Fraga ; Ranheim, Erik A. ; Johnson, Kirby D. ; Bresnick, Emery H. / Human leukemia mutations corrupt but do not abrogate GATA-2 function. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 43. pp. E10109-E10118.
@article{9e7b0cf5a6a347cf9487e5ffbcb2e88b,
title = "Human leukemia mutations corrupt but do not abrogate GATA-2 function",
abstract = "By inducing the generation and function of hematopoietic stem and progenitor cells, the master regulator of hematopoiesis GATA- 2 controls the production of all blood cell types. Heterozygous GATA2 mutations cause immunodeficiency, myelodysplastic syndrome, and acute myeloid leukemia. GATA2 disease mutations commonly disrupt amino acid residues that mediate DNA binding or cis-elements within a vital GATA2 intronic enhancer, suggesting a haploinsufficiency mechanism of pathogenesis. Mutations also occur in GATA2 coding regions distinct from the DNA-binding carboxyl-terminal zinc finger (C-finger), including the aminoterminal zinc finger (N-finger), and N-finger function is not established. Whether distinct mutations differentially impact GATA-2 mechanisms is unknown. Here, we demonstrate that N-finger mutations decreased GATA-2 chromatin occupancy and attenuated target gene regulation. We developed a genetic complementation assay to quantify GATA-2 function in myeloid progenitor cells from Gata2 -77 enhancer-mutant mice. GATA-2 complementation increased erythroid and myeloid differentiation. While GATA-2 disease mutants were not competent to induce erythroid differentiation of Lin-Kit + myeloid progenitors, unexpectedly, they promoted myeloid differentiation and proliferation. As the myelopoiesis-promoting activity of GATA-2 mutants exceeded that of GATA-2, GATA2 disease mutations are not strictly inhibitory. Thus, we propose that the haploinsufficiency paradigm does not fully explain GATA-2-linked pathogenesis, and an amalgamation of qualitative and quantitative defects instigated by GATA2 mutations underlies the complex phenotypes of GATA- 2-dependent pathologies.",
keywords = "AML, GATA-2, Hematopoiesis, Leukemia, MDS",
author = "Katsumura, {Koichi R.} and Charu Mehta and Hewitt, {Kyle J} and Soukup, {Alexandra A.} and {De Andrade}, {Isabela Fraga} and Ranheim, {Erik A.} and Johnson, {Kirby D.} and Bresnick, {Emery H.}",
year = "2018",
month = "10",
day = "23",
doi = "10.1073/pnas.1813015115/-/DCSupplemental",
language = "English (US)",
volume = "115",
pages = "E10109--E10118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "43",

}

TY - JOUR

T1 - Human leukemia mutations corrupt but do not abrogate GATA-2 function

AU - Katsumura, Koichi R.

AU - Mehta, Charu

AU - Hewitt, Kyle J

AU - Soukup, Alexandra A.

AU - De Andrade, Isabela Fraga

AU - Ranheim, Erik A.

AU - Johnson, Kirby D.

AU - Bresnick, Emery H.

PY - 2018/10/23

Y1 - 2018/10/23

N2 - By inducing the generation and function of hematopoietic stem and progenitor cells, the master regulator of hematopoiesis GATA- 2 controls the production of all blood cell types. Heterozygous GATA2 mutations cause immunodeficiency, myelodysplastic syndrome, and acute myeloid leukemia. GATA2 disease mutations commonly disrupt amino acid residues that mediate DNA binding or cis-elements within a vital GATA2 intronic enhancer, suggesting a haploinsufficiency mechanism of pathogenesis. Mutations also occur in GATA2 coding regions distinct from the DNA-binding carboxyl-terminal zinc finger (C-finger), including the aminoterminal zinc finger (N-finger), and N-finger function is not established. Whether distinct mutations differentially impact GATA-2 mechanisms is unknown. Here, we demonstrate that N-finger mutations decreased GATA-2 chromatin occupancy and attenuated target gene regulation. We developed a genetic complementation assay to quantify GATA-2 function in myeloid progenitor cells from Gata2 -77 enhancer-mutant mice. GATA-2 complementation increased erythroid and myeloid differentiation. While GATA-2 disease mutants were not competent to induce erythroid differentiation of Lin-Kit + myeloid progenitors, unexpectedly, they promoted myeloid differentiation and proliferation. As the myelopoiesis-promoting activity of GATA-2 mutants exceeded that of GATA-2, GATA2 disease mutations are not strictly inhibitory. Thus, we propose that the haploinsufficiency paradigm does not fully explain GATA-2-linked pathogenesis, and an amalgamation of qualitative and quantitative defects instigated by GATA2 mutations underlies the complex phenotypes of GATA- 2-dependent pathologies.

AB - By inducing the generation and function of hematopoietic stem and progenitor cells, the master regulator of hematopoiesis GATA- 2 controls the production of all blood cell types. Heterozygous GATA2 mutations cause immunodeficiency, myelodysplastic syndrome, and acute myeloid leukemia. GATA2 disease mutations commonly disrupt amino acid residues that mediate DNA binding or cis-elements within a vital GATA2 intronic enhancer, suggesting a haploinsufficiency mechanism of pathogenesis. Mutations also occur in GATA2 coding regions distinct from the DNA-binding carboxyl-terminal zinc finger (C-finger), including the aminoterminal zinc finger (N-finger), and N-finger function is not established. Whether distinct mutations differentially impact GATA-2 mechanisms is unknown. Here, we demonstrate that N-finger mutations decreased GATA-2 chromatin occupancy and attenuated target gene regulation. We developed a genetic complementation assay to quantify GATA-2 function in myeloid progenitor cells from Gata2 -77 enhancer-mutant mice. GATA-2 complementation increased erythroid and myeloid differentiation. While GATA-2 disease mutants were not competent to induce erythroid differentiation of Lin-Kit + myeloid progenitors, unexpectedly, they promoted myeloid differentiation and proliferation. As the myelopoiesis-promoting activity of GATA-2 mutants exceeded that of GATA-2, GATA2 disease mutations are not strictly inhibitory. Thus, we propose that the haploinsufficiency paradigm does not fully explain GATA-2-linked pathogenesis, and an amalgamation of qualitative and quantitative defects instigated by GATA2 mutations underlies the complex phenotypes of GATA- 2-dependent pathologies.

KW - AML

KW - GATA-2

KW - Hematopoiesis

KW - Leukemia

KW - MDS

UR - http://www.scopus.com/inward/record.url?scp=85055535809&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85055535809&partnerID=8YFLogxK

U2 - 10.1073/pnas.1813015115/-/DCSupplemental

DO - 10.1073/pnas.1813015115/-/DCSupplemental

M3 - Article

VL - 115

SP - E10109-E10118

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 43

ER -