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Functional and Molecular Dissection of Mutant Calreticulin in Myeloproliferative Neoplasms

骨髓增生性肿瘤中突变钙网蛋白的功能和分子解剖

基本信息

批准号：
10684812
负责人：
Ann Mullally
金额：
$ 40.2万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684812
关键词：
Acute Myelocytic Leukemia Acute leukemia Biochemical Bioinformatics Biology Blood Cells Blood coagulation Blood typing procedure Bone Marrow CRISPR/Cas technology Cells Chemicals Chromatin Clinic Clustered Regularly Interspaced Short Palindromic Repeats Data Dependence Development Disease Disease Progression Dissection Event FDA approved Genes Genetic Goals Hematological Disease Hematopoietic Hematopoietic stem cells Hemorrhage Human In Vitro JAK2 gene Knock-in Mouse Knock-out Knowledge Mass Spectrum Analysis Measures Mission Molecular Mutate Mutation Myelofibrosis Myeloproliferative disease Natural History Oncogenic Outcome Pathway interactions Patients Phenotype Production Prognosis Property Proteasome Inhibition Protein Biosynthesis Protein Secretion Proteomics Public Health Publishing Reagent Repression Research Risk Stem cell transplant Testing Therapeutic Transcriptional Activation Translating United States National Institutes of Health Work calreticulin curative treatments functional genomics glycosylation histone modification human disease in vivo inhibitor innovation insight mouse model multicatalytic endopeptidase complex mutant novel novel strategies novel therapeutic intervention novel therapeutics palliative pharmacologic prognostic proteostasis screening single cell sequencing thrombocytosis transcriptome translational impact treatment strategy whole genome

项目摘要

PROJECT SUMMARY Although the mechanism by which calreticulin (CALR) mutations cause myeloproliferative neoplasms (MPN) has been elucidated, there is currently a fundamental gap in translating this knowledge into innovative therapeutic strategies. The long-term goal is to advance the treatment of CALR-mutant MPN, in particular to develop new therapies with disease-modifying activity and curative potential. The overall objective in this application is to exploit the insights we have gained from understanding the altered biochemical properties and unique molecular dependencies of mutant CALR-driven MPN, to identify novel therapeutic vulnerabilities, including in the context of CALR/ASXL1 co-mutation. The central hypothesis is that CALR-mutant hematopoietic stem cells (HSC) have unique properties, which arise as a consequence of the mechanism of oncogenicity of mutant CALR, which we have previously elucidated. The specific properties, which we hypothesize that CALR-mutant HSC possess, include altered protein homeostasis and a differential dependency on key cellular pathways (e.g. N-glycosylation and protein secretion) for survival. We further hypothesize that co-operating genetic events (e.g. concomitant ASXL1 mutation) alter the chromatin state of CALR-mutant HSC to drive disease progression in MPN. The rationale for the proposed research is that, once we develop novel therapeutic strategies to target the unique properties of CALR-mutant HSC, we will be able to preferentially target CALR-mutant MPN cells in patients. This has the potential to alter the natural history of CALR-mutant MPN, including in the context of ASXL1 co-mutation, which confers a negative prognostic impact on CALR-mutant MPN. Guided by strong preliminary data, the hypothesis will be tested by pursuing three specific aims: 1) Determine protein homeostasis and sensitivity to proteasome inhibition in Calr-mutant HSC; 2) Determine the molecular vulnerabilities of mutant CALR-driven MPN; and 3) Determine the impact of mutant Asxl1 on Calr-mutant MPN in vivo. Under the first aim, a mutant CALR knockin (KI) mouse model that closely recapitulates the features of human CALR-mutant MPN will be employed to measure protein synthesis and proteasome activity in Calr-mutant HSC and to determine if Calr- mutant HSC are differentially sensitive to in vivo proteasome inhibition. Under the second aim, key cellular pathways we have found to be uniquely required for the survival of mutant CALR-expressing hematopoietic cells in an in vitro whole genome CRISPR knockout screen, will be inhibited using functional genetic and pharmacological approaches in mutant CALR KI mice. Under the third aim, the impact of mutant Asxl1 on histone modifications, chromatin state and the transcriptome of Calr-mutant HSC, will be determined using a mutant Asxl1 KI mouse. The approach is innovative through the application of novel murine models, in vitro and in vivo CRISPR/Cas9 gene editing, chemical screening and mass spectrometry (MS)-based quantitative proteomics. The proposed research is significant because it will uncover novel therapeutic vulnerabilities in CALR-mutant MPN. Ultimately, such knowledge has the potential to be transformative in the treatment of this disease.

项目总结

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Busy signal: platelet-derived growth factor activation in myelofibrosis.

忙碌信号：骨髓纤维化中血小板衍生生长因子的激活。

DOI：
10.3324/haematol.2020.253708
发表时间：
2020
期刊：
Haematologica
影响因子：
10.1
作者：
Marneth,AnnaE;Mullally,Ann
通讯作者：
Mullally,Ann

Biology and therapeutic targeting of molecular mechanisms in MPNs.

MPN 分子机制的生物学和治疗靶向。

DOI：
10.1182/blood.2022017416
发表时间：
2023-04-20
期刊：
BLOOD
影响因子：
20.3
作者：
How, Joan;Garcia, Jacqueline S.;Mullally, Ann
通讯作者：
Mullally, Ann

JAK2 (and other genes) be nimble with MPN diagnosis, prognosis, and therapy.

JAK2（和其他基因）可灵活用于 MPN 诊断、预后和治疗。

DOI：
10.1182/asheducation-2018.1.110
发表时间：
2018
期刊：
Hematology. American Society of Hematology. Education Program
影响因子：
0
作者：
Ciboddo,Michele;Mullally,Ann
通讯作者：
Mullally,Ann

Both sides now: losses and gains of mutant CALR.

现在双方：变异CALR的损失和收益。

DOI：
10.1182/blood.2019003820
发表时间：
2020
期刊：
Blood
影响因子：
20.3
作者：
Mullally,Ann
通讯作者：
Mullally,Ann

Distinct effects of ruxolitinib and interferon-alpha on murine JAK2V617F myeloproliferative neoplasm hematopoietic stem cell populations.

DOI：
10.1038/s41375-019-0638-y
发表时间：
2020-04
期刊：
LEUKEMIA
影响因子：
11.4
作者：
Austin, Rebecca J.;Straube, Jasmin;Bruedigam, Claudia;Pali, Gabor;Jacquelin, Sebastien;Vu, Therese;Green, Joanne;Graesel, Julius;Lansink, Lianne;Cooper, Leanne;Lee, Shin-Jye;Chen, Nien-Tsu;Lee, Chung-Wei;Haque, Ashraful;Heidel, Florian H.;D'Andrea, Richard;Hill, Geoff R.;Mullally, Ann;Milsom, Michael D.;Bywater, Megan;Lane, Steven W.
通讯作者：
Lane, Steven W.