Authors

  • Oleksandra Bondarenko
    Boston, Massachusetts, USA

DOI:

https://doi.org/10.37547/tajiir/Volume07Issue07-02

Keywords:

acute myeloid leukemia MYB proteasomal degradation PROTAC

Abstract

This study examines targeted degradation of the transcription factor MYB as a novel therapeutic avenue in acute myeloid leukemias. Its relevance stems from the limited efficacy of existing treatment regimens and the emergence of drug‐resistant disease forms. The work’s novelty lies in the integrated comparison of genetic models for MYB destabilization, chemical dTAG approaches, and the repurposing of low-molecular-weight compounds mebendazole and vitaferin A. Data are synthesized on MYB’s transformational properties critical for leukemic-clone maintenance, and experimental findings are reviewed on the suppression of transcriptional programs and induction of blast-cell death following complete factor elimination. Special attention is devoted to prospects for developing PROTAC degraders and molecular glues capable of catalyzing ubiquitin-dependent proteolysis of MYB at low compound doses. The research aims to construct a comprehensive assessment of the efficacy and safety of MYB-degradation strategies and to identify directions for further preclinical investigation. Methods include comparative analysis of peer-reviewed literature, critical appraisal of in vitro and in vivo data, and synthesis of pharmacodynamic profiles of the repurposed agents. The overall evaluation highlights the approach’s potential to overcome therapeutic resistance and improve patient survival. The findings will interest pharmacologists, oncologists, clinical researchers, and specialists in chemical biology.


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Type

Original Research

PAGE NO.

08-15

DOI

10.37547/tajiir/Volume07Issue07-02



OPEN ACCESS

SUBMITED

25 June 2025

ACCEPTED

30 June 2025

PUBLISHED

05 July 2025

VOLUME

Vol.07 Issue 07 2025

CITATION

Oleksandra Bondarenko. (2025). Targeted Degradation of MYB as a Novel
Therapeutic Strategy for Acute Myeloid Leukemias. The American Journal
of Interdisciplinary Innovations and Research, 7(07), 8

15.

https://doi.org/10.37547/tajiir/Volume07Issue07-02

COPYRIGHT

© 2025 Original content from this work may be used under the terms
of the creative commons attributes 4.0 License.

Targeted Degradation of
MYB as a Novel
Therapeutic Strategy for
Acute Myeloid Leukemias

Oleksandra Bondarenko

Boston, Massachusetts, USA

Abstract:

This study examines targeted degradation of

the transcription factor MYB as a novel therapeutic
avenue in acute myeloid leukemias. Its relevance stems
from the limited efficacy of existing treatment regimens

and the emergence of drug‐resistant disease form

s. The

work’s novelty lies in the integrated comparison of

genetic models for MYB destabilization, chemical dTAG
approaches, and the repurposing of low-molecular-
weight compounds mebendazole and vitaferin A. Data

are synthesized on MYB’s transformational p

roperties

critical

for

leukemic-clone

maintenance,

and

experimental findings are reviewed on the suppression
of transcriptional programs and induction of blast-cell
death following complete factor elimination. Special
attention is devoted to prospects for developing
PROTAC degraders and molecular glues capable of
catalyzing ubiquitin-dependent proteolysis of MYB at
low compound doses. The research aims to construct a
comprehensive assessment of the efficacy and safety of
MYB-degradation strategies and to identify directions
for further preclinical investigation. Methods include
comparative analysis of peer-reviewed literature, critical
appraisal of in vitro and in vivo data, and synthesis of
pharmacodynamic profiles of the repurposed agents.
The overall eval

uation highlights the approach’s

potential to overcome therapeutic resistance and
improve patient survival. The findings will interest
pharmacologists, oncologists, clinical researchers, and
specialists in chemical biology.

Keywords:

acute myeloid leukemia, MYB, proteasomal

degradation, PROTAC, mebendazole, vitaferin A,
targeted therapy, ubiquitin, molecular glue, drug
resistance


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INTRODUCTION

Acute myeloid leukemia (AML) remains a challenging
disease to cure: escalating chemotherapy regimens no
longer improve outcomes, prompting researchers to
focus on selectively suppressing factors that sustain
blast proliferation. The transcription factor MYB, which
governs

self-renewal

and

differentiation

of

hematopoietic stem cells, becomes hyperactivated in
certain contexts

—particularly in MLL‐rearranged

leukemias

forming pathogenic expression networks

that block maturation and drive unchecked growth. In
experimental models, MYB elimination induces

leukemic‐cell death, designating this protein as a high‐

priority target for novel therapeutic development.

Early intervention strategies aimed to disrupt the MYB

CBP/P300 complex: natural triterpenoids celastrol and
plumbagin, alongside synthetic naphthol derivatives,
impeded coactivator recruitment, weakened the
transcriptional

program,

and

inhibited

blast

proliferation. A more radical approach employed the

cell‐penetrating peptidomimetic MYBMIM, designed on

the basis of the crystal structure of the interaction
interface; MYBMIM displaces MYB from its complex,
downregulates MYC and BCL2 expression, and triggers
apoptosis. In mice bearing human AML xenografts, this
compound slowed disease progression and extended
survival. Despite these encouraging outcomes, MYB
remains present in the nucleus under this strategy,
limiting the depth of the antitumor effect.

The concept of induced proteolysis ultimately enables
complete MYB removal: heterobifunctional PROTAC
molecules simultaneously bind the target and an E3
ubiquitin ligase, initiate polyubiquitination, and shuttle
the protein to the proteasome, acting repeatedly in a
catalytic fashion. Such kinetics promise profound and
durable remissions at low doses by eradicating the
source of the transformational signal and bypassing
resistance mechanisms that arise from partial inhibition.
Consequently, targeted degradation of MYB is regarded
as the most promising avenue for creating
fundamentally new AML therapies.

The urgency of this topic is driven by the critical need for
treatments against chemoresistant AML variants and
the emergence of initial encouraging data on MYB
suppression in disease models. The aim of this article is
to analyze the current literature on targeted MYB
degradation as an AML treatment strategy, to evaluate

the scientific findings to date, and to outline prospects
for its application. The specific objectives are:

1.

To synthesize data on MYB’s role in AML

pathogenesis and on prior therapeutic attempts
targeting MYB;

2.

To

describe

key

experimental

discoveries demonstrating the feasibility of induced
MYB degradation and its effects on leukemia;

3.

To discuss the therapeutic potential of

proteasomal‐degradation technologies in comparison

with conventional treatment modalities;

4.

To assess the outlook for integrating

MYB‐degradation approaches into preclinical research

and clinical practice.

METHODS AND MATERIALS

Z. Anwar [1] delivered a systematic review of degrader
prospects in leukemia, underscoring the catalytic
mechanism inherent to the PROTAC approach. M.
Bekesh [2] examined the evolution of the PROTAC
platform and its target-selection criteria, identifying
transcription factors as the most promising candidates.
K. Klesham [3] experimentally validated the efficacy of
vitaferin A in eliminating MYB within AML cell models. T.
Harada [4] developed a dTAG system for rapid
degradation of endogenous MYB and assessed the
transcriptomic consequences of factor removal. F.

Modman [5] described mebendazole’s anti

-MYB effects,

demonstrating its potential in preclinical studies. K.
Ramaswami [6] engineered the peptidomimetic
MYBMIM and proved that displacing MYB from its p300
complex triggers blast-cell apoptosis. R. G. Ramsey [7]

investigated MYB’s roles in normal hematopoiesis

and

oncogenesis, thereby substantiating its therapeutic
appeal. V. Walf-Vorderwülbecke [8] showed that drug-
induced degradation of MYB suppresses leukemia
progression in vivo.

In preparing this article, comparative and analytical
methods were employed, coupled with a critical
synthesis of data from peer-reviewed publications,
bibliographic searches in PubMed and Web of Science,

and conceptual modeling of PROTAC technologies’

potential for clinical translation.

RESULTS

Accumulating evidence confirms that AML cells are


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critically dependent on sustained MYB expression.
Genetic deletion or silencing of MYB induces rapid
leukemic-cell death, as demonstrated in both classical
knockout models and modern induced-degradation
systems. In a recent study, researchers employed the
chemical-degron technology (dTAG system) to
selectively eradicate endogenous MYB in AML cells. By
fusing the FKBP12^F36V degron domain to the C-
terminus of MYB in the MV4-11 cell line, subsequent
treatment with the selective ligand dTAGV-1 triggered
rapid, ubiquitin-dependent proteolysis of the tagged
MYB protein. Within one hour of degrader addition,
cellular MYB levels had plummeted to near zero.
Predictably, such acute depletion of MYB resulted in a
dramatic loss of viability among leukemic cells, mirroring

the effects seen in genetic MYB knockouts [4].

Simultaneously, transcriptome analysis via SLAM-seq
revealed that removal of MYB altered transcription rates
of hundreds of genes, with predominant suppression of
those directly regulated by MYB. Notably, transcripts of
MYC, BCL2, and other MYB-dependent proto-oncogenes
were significantly reduced following MYB degradation
[6].

Thus, the in vitro induced-degradation experiment
vividly demonstrated that the oncogenic program in
AML cells collapses upon MYB elimination, leading to
clonal demise. These results substantiate the rationale
for identifying compounds capable of effecting selective
MYB degradation as a therapeutic avenue (Figure 1).

Figure 1. Major categories of proteins for which the PROTAC strategy demonstrates the greatest therapeutic

efficacy [2]

Figure 1 illustrates six classes of targets that are optimal
for proteasomal degradation. MYB falls into two of these
groups

—“undruggable” transcription factors and

scaffold

(platform)

proteins.

Such

positioning

strengthens the case for choosing MYB as a therapeutic
target and sets the stage for the development of
selective degraders described below.

Induction of MYB proteasomal degradation by drug

Tenets of
PROTAC

targets

Resistance
mutations

Undruggable

Scaffolding
function

Gene
amplification/
protein
overexpressi
on

Isoform
expression or
localization

Protein
aggregates


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repurposing. The first chemical breakthrough in
targeting MYB arose from a drug-repurposing strategy.
By comparing the gene-

expression “signature” governed

by MYB against transcriptomic profiles in the
Connectivity Map, researchers identified compounds
capable of dampening the MYB signature. One of the

strongest “hits” was mebendazole, a long

-standing

benzimidazole

antihelminthic.

In

AML

cells,

mebendazole unexpectedly reduced c-Myb protein
levels, effectively inducing its degradation via the
proteasome. Mechanistically, mebendazole disrupts the
HSP70/HSC70 chaperone system required for MYB
stability, triggering ubiquitination and proteasomal
clearance of c-Myb [8].

Notably, this effect occurs with only transient exposure:
even brief mebendazole treatment markedly impaired
leukemic-blast colony formation, while normal
hematopoietic progenitors from cord blood remained
largely unaffected. This suggests a therapeutic window
in which leukemic cells are more susceptible to MYB loss
than their normal counterparts. In vivo experiments in a
human AML xenograft model further validated

mebendazole’s promise: treated mice exhibited

significantly slower disease progression compared with

untreated controls [8]. Moreover, given mebendazole’s

extensive, well-tolerated use in humans for parasitic
infections, these data support induced MYB degradation
by mebendazole as a novel and potentially safe AML
therapy [8].

Another repurposed agent that elicits targeted MYB loss
is withaferin A (WFA), a steroidal lactone derived from
the plant Withania known for its antitumor properties.
WFA emerged as a top hit alongside mebendazole in the
Connectivity Map screen for MYB-suppressive activity.
Recent work has shown that WFA induces rapid and
pronounced ablation of c-Myb in AML cells [3]. Within
hours of treatment, MYB protein levels fall to nearly
undetectable levels and transcription of MYB-target
genes is suppressed. WFA treatment mirrors

mebendazole’s effects, triggering blast

-cell death and

inhibiting colony formation. Its mechanism likewise
involves proteostasis stress: WFA activates the
unfolded-protein

response,

destabilizing

the

HSP70/HSC70 complex and leading to c-Myb
ubiquitination and degradation. Crucially, expression of
a degradation-resistant MYB mutant partially rescues

cells from WFA-induced death, confirming the specificity
of this pathway [3].

Thus, WFA’s antileukemic action is largely mediated

through MYB depletion. In vivo, WFA treatment of AML-
bearing mice slowed disease progression and reduced

leukemic burden. Given WFA’s historical use in

traditional medicine and established human exposure,
its repurposing for AML therapy represents a highly
attractive direction [3].

A distinguishing feature of the MYB-degradation
strategy is the complete removal of the oncoprotein
from the cell, whereas traditional approaches merely
block its function while leaving the protein intact.
Experience with direct MYB inhibitors shows their
limited efficacy due to incomplete target suppression
and off-target effects. For instance, small molecules that
disrupt the MYB

p300 interaction (celastrol, plumbagin,

etc.) and the peptidomimetic MYBMIM partially inhibit

MYB’s transcriptional activity and slow leukemic

-cell

growth [6]. However, a recent comparative analysis of
these agents revealed significant drawbacks: purported
MYB inhibitors exhibit only partial specificity and induce
substantial collateral effects on the expression of
unrelated genes. Moreover, some of these compounds
were unexpectedly found to act in a dual manner

alongside inhibiting certain MYB functions, they
paradoxically stimulate the expression of other MYB-
regulated genes, functioning as mixed agonist

antagonists. These unforeseen activities complicate the
clinical use of direct MYB inhibitors [6].

In contrast, targeted degradation eliminates MYB as a
factor, theoretically obviating the risk of residual protein
exerting excessive or compensatory activity. Indeed, in
the described models, treatment with degraders
(mebendazole, WFA) yielded unequivocal suppression
of MYB-driven transcriptional programs and rapid cell
death, with no signs of paradoxical oncogenic pathway
activation [3; 8]. These findings suggest that a
degradation-based strategy may be both more effective
and more specific than traditional MYB inhibitors.

Different pharmacological paradigms vary in their
specificity and clinical applicability. Comparing the
approaches reported in the literature allows an
assessment of the potential gains from adopting
targeted-degradation technologies (Table 1).


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Table 1

Comparative analysis of therapeutic approaches in AML (compiled by the author based on [1

8])

Approach

Target

Mode of

Action

Selectivity

Advantages

Limitations

Chemotherapy

DNA
synthesis

Cytotoxicity

Low

Effective against
rapidly dividing
cells

Myelosuppression;
resistance

FLT3 inhibitors

Activated
kinase

Enzymatic
blockade

Medium

Subtype-specific
activity

Secondary
mutations

MYB

p300

interaction
inhibitors

Protein

protein

Coactivator
disruption

Medium

Disrupts
transcriptional
complex

Partial

MYB

suppression;

off-

target effects [6]

Mebendazole/WFA
repurposing

MYB

Induced
degradation

High

Uses

approved

drugs;

known

safety profiles

Dose-dependent
off-target activity
[3; 8]

PROTAC degraders
targeting MYB

MYB

Proteasomal
degradation

Very high

Catalytic action
at low doses

Requires
pharmacokinetic
optimization

Comparison shows that MYB removal outperforms
traditional regimens both in selectivity and depth of
tumor-clone suppression. This advantage stems from

the leukemic cell’s inability to compensate for loss of

a

central transcriptional node, whereas kinase inhibition
often leads to escape signaling.

In summary, the review of experimental data
demonstrates the practical feasibility and high efficacy
of targeted MYB degradation in AML models. Induced
proteasomal elimination of MYB

whether via

dedicated chemical degraders or repurposed agents

triggers collapse of the oncogenic program and
eradication of leukemic cells in vitro and in vivo. These
findings lay the groundwork for developing a new class
of therapeutics aimed at eliminating MYB in resistant
AML forms.

DISCUSSION

The findings presented here must be viewed in the
context of developing novel antileukemic therapies.
Targeted

degradation

of

MYB

represents

a

fundamentally different strategy, aimed at the root of
the oncogenic process

the pathological transcriptional

network sustained by MYB. Unlike traditional cytotoxic
agents, which nonspecifically target dividing cells, or
kinase inhibitors that block individual signaling
pathways, eradication of a key transcription factor
promises simultaneous suppression of multiple
oncogenic gene targets. In the case of MYB, these
include critical drivers of proliferation and survival (such
as MYC and BCL2) as well as factors that inhibit cellular
differentiation. Consequently, MYB removal can induce
both differentiation and apoptosis of leukemic blasts, as
experimentally evidenced by mitochondrial apoptotic
markers and signs of cellular maturation upon MYB
suppression. This multi-targeted impact on the gene
network renders MYB degradation a potent weapon
against leukemia, potentially surpassing traditional
modalities in depth of effect.

Thus, MYB degradation effectively “knocks out” the

central hub upon which the malignant clone depends, a
scenario fundamentally distinct from the action of
narrowly focused agents (e.g., FLT3 or IDH mutation
inhibitors), whose efficacy is confined to tumor
subpopulations and often wanes with the emergence of
secondary mutations. By contrast, MYB elimination


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theoretically leaves leukemic cells no compensatory
route, as it concurrently disrupts multiple oncogenic
pathways.

From a practical standpoint, the targeted-degradation
platform is advancing rapidly and already moving
beyond the confines of the laboratory. PROTAC
technology, as noted, has given rise to numerous
experimental degraders against various oncoproteins
[1]. Notably, the first examples are now appearing in
oncohematology: PROTACs targeting the proto-
oncogene STAT3, oncogenic kinases, and epigenetic
regulators are under development, with several
progressing through preclinical evaluation. Although no
MYB-specific PROTAC has yet been disclosed, all the

elements for its design are in place. As a “warhead”—

the

binding

moiety

one

might

employ

the

peptidomimetic MYBMIM or another small molecule

that disrupts the MYB

p300 interaction. By linking such

a ligand to an appropriate linker and an E3-ligase
recruiting moiety (for example, CRBN or VHL), it would
be possible to craft a bifunctional degrader capable of
recruiting the E3 ligase to MYB and marking it for
proteasomal destruction. Given the success of PROTACs
in other models, a parallel approach against MYB is
anticipated to yield a potent antileukemic agent.

The PROTAC system has opened the door to the
selective elimination of nuclear oncoproteins once

considered “undruggable” by conventional small

-

molecule inhibitors. A chimeric PROTAC simultaneously
engages the target factor and an E3 ligase, forming a
transient

ternary

complex

that

initiates

polyubiquitination

and

subsequent

proteasomal

degradation (Figure 2).

Figure 2. Sequence of events in PROTAC-

induced MYB degradation: disease → target → tool → proteasomal

removal → blast differentiation and apoptosis (compiled by the author based on [2])

Comparing the proposed strategy with conventional
AML treatments highlights several aspects. Standard
chemotherapy

based

on

antimetabolites

and

cytotoxins

lacks molecular specificity: it attacks all

rapidly dividing cells, causing severe side effects and
failing to guarantee eradication of the leukemic clone,

particularly when the tumor harbors stem cells with low
proliferative

activity.

Allogeneic

bone-marrow

transplantation can achieve radical cure through graft-
versus-leukemia immunity but entails high mortality and
serious complications. Targeted agents against mutant
tyrosine kinases (for example, FLT3 inhibitors) and

[Chemoresistant ALL]

[MYB - pathologic transcriptional network node]

[PROTAC-degrador: WARHEAD-linker-E3]

[MYB proteasomal elimination]

[↓ MYC, BCL2 → blast differentiation and apoptosis]


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epigenetic enzymes (IDH1/2 inhibitors) benefit only the
corresponding patient subgroups and, while they often
induce remission, do not prevent relapse when used as
monotherapy. Against this backdrop, the MYB-
degradation

strategy

distinguishes

itself

by

universality

MYB is active across many AML subtypes,

including cases without “druggable” mutations.

Moreover, it directly targets the fundamental
mechanism sustaining leukemia. Of course, risks must
be acknowledged: MYB is essential for normal
hematopoiesis, so systemic MYB suppression may lead
to myelosuppression and aplastic states. However,
hematologists are accustomed to this challenge

intensive chemotherapy likewise ablates bone marrow,
and clinicians manage the effect via transplantation or
growth-factor support.

From the standpoint of in vivo efficacy and clinical
translation, the first positive signals have already
emerged. Mebendazole repurposing advanced rapidly
to clinical evaluation thanks to its prior approval for
other indications. In particular, clinical trials combining
mebendazole with low-dose cytarabine in elderly and
refractory AML patients are being initiated [5]. This
regimen is designed to harness synergy: mebendazole
both directly undermines blast survival through MYB
(and other factor) degradation and increases residual

cells’ sensitivity to chemotherapeutics.

PROTAC platform technologies are already in early
clinical studies for a variety of targets

such as

androgen-receptor degraders in prostate cancer and
estrogen-receptor degraders in breast cancer [2]. In
oncohematology, efforts are also underway: for
example, a PROTAC against BCL-XL, intended to treat
leukemias without platelet toxicity, and degraders of
fusion oncoproteins have been announced. Although
specific data on a MYB-targeting PROTAC have not yet
appeared, successes in related fields make the
development of such molecules highly likely.
Preclinically, they could be evaluated in human AML
xenografts in immunodeficient mice (PDX models),
where MYBMIM, mebendazole, and WFA have already
demonstrated proof of concept.

CONCLUSION

The advancement of a targeted MYB-degradation
strategy heralds a new chapter in acute myeloid
leukemia therapy. Existing studies compellingly

demonstrate the scientific merit of this approach: they

confirm MYB’s central role in maintaining the malignant

AML phenotype and show that MYB elimination halts
proliferation and induces leukemic-cell death. From a
practical standpoint, MYB degradation offers an
innovative solution to overcome drug resistance. In
cases where tumors fail to respond to chemotherapy,
direct removal of the transcriptional oncogene may

deliver a “knockout” blow from which c

ancer cells

cannot recover. This is especially relevant in refractory
AML subtypes, where alternative targets may be absent
or play only secondary roles.

In vitro and in vivo data indicate that proteasomal
clearance of MYB achieves selective eradication of the
leukemic clone while sparing normal hematopoietic
progenitors to a large extent. These findings provide
strong justification for continued development of this
approach. Repurposing existing agents (such as
mebendazole) accelerates the transition to clinical
evaluation, while emerging platforms (PROTACs,
molecular glues) expand the toolkit for directing the
proteasome against MYB. Integration of MYB-
degradation strategies into the preclinical pipeline is
already underway: advanced animal studies are in
progress,

and

combination

regimens

with

chemotherapy are being optimized. In the near term,
initial clinical trial results can be expected to clarify the
feasibility and efficacy of this approach in patients.

In summary, targeted MYB degradation has established
itself as a promising AML treatment modality capable of
complementing and potentially surpassing conventional
regimens in resistant disease forms. If subsequent trials
confirm the safety and effectiveness of MYB
degradation, this strategy may assume a prominent
place in the antileukemic armamentarium

paving the

way to more durable remissions and cures for patients
who have exhausted existing options.

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