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Article ; Online: Enhanced MAPK signaling induced by CSF3Rmutants confers dependence to DUSP1 for leukemic transformation.

Kesarwani, Meenu / Kincaid, Zachary / Azhar, Mohammad / Azam, Mohammad

2024

Abstract: Elevated MAPK and the JAK-STAT signaling play pivotal roles in the pathogenesis of chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML). While inhibitors targeting these pathways effectively suppress the diseases, they fall ... ...

Abstract	Elevated MAPK and the JAK-STAT signaling play pivotal roles in the pathogenesis of chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML). While inhibitors targeting these pathways effectively suppress the diseases, they fall short in providing enduring remission, largely attributed to cytostatic nature of these drugs. Even combinations of these drugs are ineffective in achieving sustained remission. Enhanced MAPK signaling besides promoting proliferation and survival triggers a pro-apoptotic response. Consequently, malignancies reliant on elevated MAPK signaling employ MAPK-feedback regulators to intricately modulate the signaling output, prioritizing proliferation and survival while dampening the apoptotic stimuli. Herein, we demonstrate that enhanced MAPK signaling in CSF3R (Granulocyte-colony stimulating factor receptor)-driven leukemia upregulates the expression of Dual specificity phosphatase 1 (DUSP1) to suppress the apoptotic stimuli crucial for leukemogenesis. Consequently, genetic deletion of Dusp1 in mice conferred synthetic lethality to CSF3R-induced leukemia. Mechanistically, DUSP1 depletion in leukemic context causes activation of JNK1/2 that results in induced expression of BIM and P53 while suppressing the expression BCL2 that selectively triggers apoptotic response in leukemic cells. Pharmacological inhibition of DUSP1 by BCI (a DUSP1 inhibitor) alone lacked anti-leukemic activity due to ERK1/2 rebound caused by off-target inhibition of DUSP6. Consequently, a combination of BCI with a MEK inhibitor successfully cured CSF3R-induced leukemia in a preclinical mouse model. Our findings underscore the pivotal role of DUSP1 in leukemic transformation driven by enhanced MAPK signaling and advocate for the development of a selective DUSP1 inhibitor for curative treatment outcomes.
Language	English
Publishing date	2024-03-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2023010830
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Book ; Online: Solvable Polynomial Ideals

Cyphert, John / Kincaid, Zachary

The Ideal Reflection for Program Analysis

2023

Abstract: This paper presents a program analysis method that generates program summaries involving polynomial arithmetic. Our approach builds on prior techniques that use solvable polynomial maps for summarizing loops. These techniques are able to generate all ... ...

Abstract	This paper presents a program analysis method that generates program summaries involving polynomial arithmetic. Our approach builds on prior techniques that use solvable polynomial maps for summarizing loops. These techniques are able to generate all polynomial invariants for a restricted class of programs, but cannot be applied to programs outside of this class -- for instance, programs with nested loops, conditional branching, unstructured control flow, etc. There currently lacks approaches to apply these prior methods to the case of general programs. This paper bridges that gap. Instead of restricting the kinds of programs we can handle, our method abstracts every loop into a model that can be solved with prior techniques, bringing to bear prior work on solvable polynomial maps to general programs. While no method can generate all polynomial invariants for arbitrary programs, our method establishes its merit through a monotonicty result. We have implemented our techniques, and tested them on a suite of benchmarks from the literature. Our experiments indicate our techniques show promise on challenging verification tasks requiring non-linear reasoning. Comment: Long version of an article to appear at the 51st ACM SIGPLAN Symposium on Principles of Programming Languages (POPL 2024). This version is a replacement of an earlier long version where typos have been fixed, DOI's have been added to references when able, and a data availability statement has been added
Keywords	Computer Science - Programming Languages
Subject code	000
Publishing date	2023-11-07
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Book ; Online: Termination Analysis Without the Tears

Zhu, Shaowei / Kincaid, Zachary

2021

Abstract: Determining whether a given program terminates is the quintessential undecidable problem. Algorithms for termination analysis are divided into two groups: (1) algorithms with strong behavioral guarantees that work in limited circumstances (e.g., complete ...

Abstract	Determining whether a given program terminates is the quintessential undecidable problem. Algorithms for termination analysis are divided into two groups: (1) algorithms with strong behavioral guarantees that work in limited circumstances (e.g., complete synthesis of linear ranking functions for polyhedral loops [Podelski and Rybalchenko, 2004]), and (2) algorithms that are widely applicable, but have weak behavioral guarantees (e.g., Terminator [Cook et al., 2006]). This paper investigates the space in between: how can we design practical termination analyzers with useful behavioral guarantees? This paper presents a termination analysis that is both compositional (the result of analyzing a composite program is a function of the analysis results of its components) and monotone ("more information into the analysis yields more information out"). The paper has two key contributions. The first is an extension of Tarjan's method for solving path problems in graphs to solve infinite path problems. This provides a foundation upon which to build compositional termination analyses. The second is a collection of monotone conditional termination analyses based on this framework. We demonstrate that our tool ComPACT (Compositional and Predictable Analysis for Conditional Termination) is competitive with state-of-the-art termination tools while providing stronger behavioral guarantees.
Keywords	Computer Science - Programming Languages
Subject code	005
Publishing date	2021-01-24
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Book ; Online: Loop Summarization with Rational Vector Addition Systems (extended version)

Silverman, Jake / Kincaid, Zachary

2019

Abstract: This paper presents a technique for computing numerical loop summaries. The method synthesizes a rational vector addition system with resets (Q-VASR) that simulates the action of an input loop, and then uses the reachability relation of that Q-VASR to ... ...

Abstract	This paper presents a technique for computing numerical loop summaries. The method synthesizes a rational vector addition system with resets (Q-VASR) that simulates the action of an input loop, and then uses the reachability relation of that Q-VASR to over-approximate the behavior of the loop. The key technical problem solved in this paper is to automatically synthesize a Q-VASR that is a best abstraction of a given loop in the sense that (1) it simulates the loop and (2) it is simulated by any other Q-VASR that simulates the loop. Since our loop summarization scheme is based on computing the exact reachability relation of a best abstraction of a loop, we can make theoretical guarantees about its behavior. Moreover, we show experimentally that the technique is precise and performant in practice.
Keywords	Computer Science - Programming Languages
Publishing date	2019-05-15
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Methods for evaluating the role of c-fos and dusp1 in oncogene dependence

Kesarwani, Meenu / Kincaid, Zachary / Azam, Mohammad

Journal of visualized experiments. 2019 Jan. 07, , no. 143

2019

Abstract: The demonstration of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML) has heralded a new era in cancer therapeutics. However, a small population of cells does not respond to TKI treatment, resulting in minimal residual disease ...

Abstract	The demonstration of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML) has heralded a new era in cancer therapeutics. However, a small population of cells does not respond to TKI treatment, resulting in minimal residual disease (MRD); even the most potent TKIs fail to eradicate these cells. These MRD cells serve as a reservoir to develop resistance to therapy. Why TKI treatment is ineffective against MRD cells is not known. Growth factor signaling is implicated in supporting the survival of MRD cells during TKI treatment, but a mechanistic understanding is lacking. Recent studies demonstrated that an elevated c-Fos and Dusp1 expression as a result of convergent oncogenic and growth factor signaling in MRD cells mediate TKI resistance. The genetic and chemical inhibition of c-Fos and Dusp1 renders CML exquisitely sensitive to TKIs and cures CML in both genetic and humanized mouse models. We identified these target genes using multiple microarrays from TKI-sensitive and -resistant cells. Here, we provide methods for target validation using in vitro and in vivo mouse models. These methods can easily be applied to any target for genetic validation and therapeutic development.
Keywords	animal models ; enzyme inhibitors ; microarray technology ; myeloid leukemia ; oncogenes ; therapeutics ; tyrosine
Language	English
Dates of publication	2019-0107
Size	p. e58194.
Publishing place	Journal of Visualized Experiments
Document type	Article
ZDB-ID	2259946-0
ISSN	1940-087X
ISSN	1940-087X
DOI	10.3791/58194
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence.

Kesarwani, Meenu / Kincaid, Zachary / Azam, Mohammad

Journal of visualized experiments : JoVE

2019 , Issue 143

Abstract	The demonstration of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML) has heralded a new era in cancer therapeutics. However, a small population of cells does not respond to TKI treatment, resulting in minimal residual disease (MRD); even the most potent TKIs fail to eradicate these cells. These MRD cells serve as a reservoir to develop resistance to therapy. Why TKI treatment is ineffective against MRD cells is not known. Growth factor signaling is implicated in supporting the survival of MRD cells during TKI treatment, but a mechanistic understanding is lacking. Recent studies demonstrated that an elevated c-Fos and Dusp1 expression as a result of convergent oncogenic and growth factor signaling in MRD cells mediate TKI resistance. The genetic and chemical inhibition of c-Fos and Dusp1 renders CML exquisitely sensitive to TKIs and cures CML in both genetic and humanized mouse models. We identified these target genes using multiple microarrays from TKI-sensitive and -resistant cells. Here, we provide methods for target validation using in vitro and in vivo mouse models. These methods can easily be applied to any target for genetic validation and therapeutic development.
MeSH term(s)	Animals ; Dual Specificity Phosphatase 1/genetics ; Humans ; Mice ; Proto-Oncogene Proteins c-fos/genetics
Chemical Substances	Proto-Oncogene Proteins c-fos ; DUSP1 protein, human (EC 3.1.3.48) ; Dual Specificity Phosphatase 1 (EC 3.1.3.48)
Language	English
Publishing date	2019-01-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Video-Audio Media
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/58194
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Book ; Online: Templates and Recurrences

Breck, Jason / Cyphert, John / Kincaid, Zachary / Reps, Thomas

Better Together

2020

Abstract: This paper is the confluence of two streams of ideas in the literature on generating numerical invariants, namely: (1) template-based methods, and (2) recurrence-based methods. A template-based method begins with a template that contains unknown ... ...

Abstract	This paper is the confluence of two streams of ideas in the literature on generating numerical invariants, namely: (1) template-based methods, and (2) recurrence-based methods. A template-based method begins with a template that contains unknown quantities, and finds invariants that match the template by extracting and solving constraints on the unknowns. A disadvantage of template-based methods is that they require fixing the set of terms that may appear in an invariant in advance. This disadvantage is particularly prominent for non-linear invariant generation, because the user must supply maximum degrees on polynomials, bases for exponents, etc. On the other hand, recurrence-based methods are able to find sophisticated non-linear mathematical relations, including polynomials, exponentials, and logarithms, because such relations arise as the solutions to recurrences. However, a disadvantage of past recurrence-based invariant-generation methods is that they are primarily loop-based analyses: they use recurrences to relate the pre-state and post-state of a loop, so it is not obvious how to apply them to a recursive procedure, especially if the procedure is non-linearly recursive (e.g., a tree-traversal algorithm). In this paper, we combine these two approaches and obtain a technique that uses templates in which the unknowns are functions rather than numbers, and the constraints on the unknowns are recurrences. The technique synthesizes invariants involving polynomials, exponentials, and logarithms, even in the presence of arbitrary control-flow, including any combination of loops, branches, and (possibly non-linear) recursion. For instance, it is able to show that (i) the time taken by merge-sort is $O(n \log(n))$, and (ii) the time taken by Strassen's algorithm is $O(n^{\log_2(7)})$. Comment: 20 pages, 3 figures
Keywords	Computer Science - Programming Languages
Subject code	005
Publishing date	2020-03-30
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: MEK/ERK addiction in CNL/aCML.

Kesarwani, Meenu / Kincaid, Zachary / Azam, Mohammad

Oncotarget

2017 Volume 8, Issue 59, Page(s) 99215–99216

Language	English
Publishing date	2017-11-03
Publishing country	United States
Document type	Editorial
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.22283
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: MAPK-negative feedback regulation confers dependence to JAK2

Kesarwani, Meenu / Kincaid, Zachary / Azhar, Mohammad / Menke, Jacob / Schwieterman, Joshua / Ansari, Sekhu / Reaves, Angela / Deininger, Michael E / Levine, Ross / Grimes, H Leighton / Azam, Mohammad

Leukemia

2023 Volume 37, Issue 8, Page(s) 1686–1697

Abstract: Despite significant advances in developing selective JAK2 inhibitors, JAK2 kinase inhibitor (TKI) therapy is ineffective in suppressing the disease. Reactivation of compensatory MEK-ERK and PI3K survival pathways sustained by inflammatory cytokine ... ...

Abstract	Despite significant advances in developing selective JAK2 inhibitors, JAK2 kinase inhibitor (TKI) therapy is ineffective in suppressing the disease. Reactivation of compensatory MEK-ERK and PI3K survival pathways sustained by inflammatory cytokine signaling causes treatment failure. Concomitant inhibition of MAPK pathway and JAK2 signaling showed improved in vivo efficacy compared to JAK2 inhibition alone but lacked clonal selectivity. We hypothesized that cytokine signaling in JAK2
MeSH term(s)	Humans ; Feedback ; Tumor Suppressor Protein p53/metabolism ; Signal Transduction ; Antineoplastic Agents/therapeutic use ; Cytokines/metabolism ; Janus Kinase 2/metabolism ; Myeloproliferative Disorders/drug therapy ; Mutation
Chemical Substances	Tumor Suppressor Protein p53 ; Antineoplastic Agents ; Cytokines ; Janus Kinase 2 (EC 2.7.10.2) ; JAK2 protein, human (EC 2.7.10.2)
Language	English
Publishing date	2023-07-10
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-023-01959-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Momelotinib is a highly potent inhibitor of FLT3-mutant AML.

Azhar, Mohammad / Kincaid, Zachary / Kesarwani, Meenu / Ahmed, Arhama / Wunderlich, Mark / Latif, Tahir / Starczynowski, Daniel / Azam, Mohammad

Blood advances

2021 Volume 6, Issue 4, Page(s) 1186–1192

Abstract: Despite the introduction of more selective FLT3 inhibitors to treat FLT3-mutated acute myeloid leukemia (AML), remissions are short lived, and patients show progressive disease after an initial response. Acquisition of resistance-conferring genetic ... ...

Abstract	Despite the introduction of more selective FLT3 inhibitors to treat FLT3-mutated acute myeloid leukemia (AML), remissions are short lived, and patients show progressive disease after an initial response. Acquisition of resistance-conferring genetic mutations and growth factor signaling are 2 principal mechanisms that drive relapse. FLT3 inhibitors targeting both escape mechanisms could lead to a more profound and lasting clinical response. Here, we show that the JAK2 inhibitor momelotinib is an equipotent type 1 FLT3 inhibitor. Momelotinib showed potent inhibition of FLT3-internal tandem duplication in mouse and human primary cells and effectively suppressed its clinically relevant resistant variants within the activation loop at residues D835, D839, and Y842. Additionally, momelotinib efficiently suppressed the resistance mediated by growth factors and hematopoietic cytokine-activated JAK2 signaling. Consequently, concomitant inhibition of FLT3 and suppression of growth factor signaling by momelotinib treatment showed better efficacy in suppressing leukemia in a preclinical murine model of AML. Altogether, these data provide evidence that momelotinib is an effective type 1 dual JAK2/FLT3 inhibitor and may offer an alternative to gilteritinib. Its ability to impede the resistance conferred by growth factor signaling and activation loop mutants suggests that momelotinib treatment could provide a deeper and durable response and, thus, warrants its clinical evaluation.
MeSH term(s)	Animals ; Benzamides ; Cell Line, Tumor ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Mice ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Pyrimidines/therapeutic use ; fms-Like Tyrosine Kinase 3/genetics ; fms-Like Tyrosine Kinase 3/therapeutic use
Chemical Substances	Benzamides ; Protein Kinase Inhibitors ; Pyrimidines ; N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide (6O01GMS00P) ; FLT3 protein, human (EC 2.7.10.1) ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1)
Language	English
Publishing date	2021-11-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2021004611
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