A STAT3 degrader demonstrates efficacy in venetoclax resistant acute myeloid leukemia

Samarpana Chakraborty; Claudia Morganti; Kimberly Zaldana; Bianca Rivera Pena; Hui Zhang; Divij Verma; Nadege Gitego; Feiyang Ma; Srinivas Aluri; Kith Pradhan; Shanisha Gordon-Mitchell; Ioannis Mantzaris; Mendel Goldfinger; Eric Feldman; Kira Gritsman; Yang Shi; Stefan Hubner; Yi Hua Qiu; Brandon D. Brown; Abdullah Khasawneh; Anna Skwarska; Eduardo Sabino de Camargo Magalhães; Amit Verma; Marina Konopleva; Yoko Tabe; Evripidis Gavathiotis; Simona Colla; Jared Gollob; Joyoti Dey; Steven M. Kornblau; Sergei B. Koralov; Keisuke Ito; Aditi Shastri

doi:10.1038/s41375-026-02883-9

A STAT3 degrader demonstrates efficacy in venetoclax resistant acute myeloid leukemia

Samarpana Chakraborty
, Claudia Morganti
, Kimberly Zaldana
, Bianca Rivera Pena
, Hui Zhang
, Divij Verma
, Nadege Gitego
, Feiyang Ma
, Srinivas Aluri
, Kith Pradhan
, Shanisha Gordon-Mitchell
, Ioannis Mantzaris
, Mendel Goldfinger
, Eric Feldman
, Kira Gritsman
, Yang Shi
, Stefan Hubner
, Yi Hua Qiu
, Brandon D. Brown
, Abdullah Khasawneh

Anna Skwarska, Eduardo Sabino de Camargo Magalhães, Amit Verma, Marina Konopleva, Yoko Tabe, Evripidis Gavathiotis, Simona Colla, Jared Gollob, Joyoti Dey, Steven M. Kornblau, Sergei B. Koralov, Keisuke Ito, Aditi Shastri

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Acute myeloid leukemia (AML) is an aggressive myeloid malignancy with a poor prognosis. Venetoclax (Ven), a BCL2 inhibitor, has shown promising results but often leads to relapse due to mitochondrial dysregulation, particularly due to upregulation of the anti-apoptotic protein MCL1. Overexpression of the transcription factor STAT3 has been linked to poor survival in AML patients. Overexpression of STAT3 in a transgenic murine model induces a myeloid malignancy with a short latency period and inflammatory upregulation. The current study identifies STAT3 upregulation as a key mechanism of Ven resistance. A clinically relevant STAT3 degrader effectively reduces both total and phosphorylated STAT3, corrects mitochondrial structural and functional dysregulation, and induces apoptosis in Ven-resistant AML cell lines. KT-333 significantly decreases STAT3 and MCL1 protein levels and improves survival in Ven-resistant (Ven-Res) AML murine models. In summary, STAT3 hyperactivation is leukemogenic, is further potentiated in Ven-resistance and can be clinically targeted with a novel and specific STAT3 degrader. (Figure presented.)

Original language	English (US)
Pages (from-to)	717-729
Number of pages	13
Journal	Leukemia
Volume	40
Issue number	4
DOIs	https://doi.org/10.1038/s41375-026-02883-9
State	Published - Apr 2026

ASJC Scopus subject areas

Hematology
Oncology
Cancer Research

Access to Document

10.1038/s41375-026-02883-9

Cite this

Chakraborty, S., Morganti, C., Zaldana, K., Rivera Pena, B., Zhang, H., Verma, D., Gitego, N., Ma, F., Aluri, S., Pradhan, K., Gordon-Mitchell, S., Mantzaris, I., Goldfinger, M., Feldman, E., Gritsman, K., Shi, Y., Hubner, S., Qiu, Y. H., Brown, B. D., ... Shastri, A. (2026). A STAT3 degrader demonstrates efficacy in venetoclax resistant acute myeloid leukemia. Leukemia, 40(4), 717-729. https://doi.org/10.1038/s41375-026-02883-9

Chakraborty, S, Morganti, C, Zaldana, K, Rivera Pena, B, Zhang, H, Verma, D, Gitego, N, Ma, F, Aluri, S, Pradhan, K, Gordon-Mitchell, S, Mantzaris, I, Goldfinger, M, Feldman, E, Gritsman, K, Shi, Y, Hubner, S, Qiu, YH, Brown, BD, Khasawneh, A, Skwarska, A, de Camargo Magalhães, ES, Verma, A, Konopleva, M, Tabe, Y, Gavathiotis, E, Colla, S, Gollob, J, Dey, J, Kornblau, SM, Koralov, SB, Ito, K & Shastri, A 2026, 'A STAT3 degrader demonstrates efficacy in venetoclax resistant acute myeloid leukemia', Leukemia, vol. 40, no. 4, pp. 717-729. https://doi.org/10.1038/s41375-026-02883-9

@article{f8fbe3e0ec2243329dc4679359c78700,

title = "A STAT3 degrader demonstrates efficacy in venetoclax resistant acute myeloid leukemia",

abstract = "Acute myeloid leukemia (AML) is an aggressive myeloid malignancy with a poor prognosis. Venetoclax (Ven), a BCL2 inhibitor, has shown promising results but often leads to relapse due to mitochondrial dysregulation, particularly due to upregulation of the anti-apoptotic protein MCL1. Overexpression of the transcription factor STAT3 has been linked to poor survival in AML patients. Overexpression of STAT3 in a transgenic murine model induces a myeloid malignancy with a short latency period and inflammatory upregulation. The current study identifies STAT3 upregulation as a key mechanism of Ven resistance. A clinically relevant STAT3 degrader effectively reduces both total and phosphorylated STAT3, corrects mitochondrial structural and functional dysregulation, and induces apoptosis in Ven-resistant AML cell lines. KT-333 significantly decreases STAT3 and MCL1 protein levels and improves survival in Ven-resistant (Ven-Res) AML murine models. In summary, STAT3 hyperactivation is leukemogenic, is further potentiated in Ven-resistance and can be clinically targeted with a novel and specific STAT3 degrader. (Figure presented.)",

author = "Samarpana Chakraborty and Claudia Morganti and Kimberly Zaldana and \{Rivera Pena\}, Bianca and Hui Zhang and Divij Verma and Nadege Gitego and Feiyang Ma and Srinivas Aluri and Kith Pradhan and Shanisha Gordon-Mitchell and Ioannis Mantzaris and Mendel Goldfinger and Eric Feldman and Kira Gritsman and Yang Shi and Stefan Hubner and Qiu, \{Yi Hua\} and Brown, \{Brandon D.\} and Abdullah Khasawneh and Anna Skwarska and \{de Camargo Magalh{\~a}es\}, \{Eduardo Sabino\} and Amit Verma and Marina Konopleva and Yoko Tabe and Evripidis Gavathiotis and Simona Colla and Jared Gollob and Joyoti Dey and Kornblau, \{Steven M.\} and Koralov, \{Sergei B.\} and Keisuke Ito and Aditi Shastri",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2026.",

year = "2026",

month = apr,

doi = "10.1038/s41375-026-02883-9",

language = "English (US)",

volume = "40",

pages = "717--729",

journal = "Leukemia",

issn = "0887-6924",

publisher = "Springer Nature",

number = "4",

}

TY - JOUR

T1 - A STAT3 degrader demonstrates efficacy in venetoclax resistant acute myeloid leukemia

AU - Chakraborty, Samarpana

AU - Morganti, Claudia

AU - Zaldana, Kimberly

AU - Rivera Pena, Bianca

AU - Zhang, Hui

AU - Verma, Divij

AU - Gitego, Nadege

AU - Ma, Feiyang

AU - Aluri, Srinivas

AU - Pradhan, Kith

AU - Gordon-Mitchell, Shanisha

AU - Mantzaris, Ioannis

AU - Goldfinger, Mendel

AU - Feldman, Eric

AU - Gritsman, Kira

AU - Shi, Yang

AU - Hubner, Stefan

AU - Qiu, Yi Hua

AU - Brown, Brandon D.

AU - Khasawneh, Abdullah

AU - Skwarska, Anna

AU - de Camargo Magalhães, Eduardo Sabino

AU - Verma, Amit

AU - Konopleva, Marina

AU - Tabe, Yoko

AU - Gavathiotis, Evripidis

AU - Colla, Simona

AU - Gollob, Jared

AU - Dey, Joyoti

AU - Kornblau, Steven M.

AU - Koralov, Sergei B.

AU - Ito, Keisuke

AU - Shastri, Aditi

PY - 2026/4

Y1 - 2026/4

N2 - Acute myeloid leukemia (AML) is an aggressive myeloid malignancy with a poor prognosis. Venetoclax (Ven), a BCL2 inhibitor, has shown promising results but often leads to relapse due to mitochondrial dysregulation, particularly due to upregulation of the anti-apoptotic protein MCL1. Overexpression of the transcription factor STAT3 has been linked to poor survival in AML patients. Overexpression of STAT3 in a transgenic murine model induces a myeloid malignancy with a short latency period and inflammatory upregulation. The current study identifies STAT3 upregulation as a key mechanism of Ven resistance. A clinically relevant STAT3 degrader effectively reduces both total and phosphorylated STAT3, corrects mitochondrial structural and functional dysregulation, and induces apoptosis in Ven-resistant AML cell lines. KT-333 significantly decreases STAT3 and MCL1 protein levels and improves survival in Ven-resistant (Ven-Res) AML murine models. In summary, STAT3 hyperactivation is leukemogenic, is further potentiated in Ven-resistance and can be clinically targeted with a novel and specific STAT3 degrader. (Figure presented.)

AB - Acute myeloid leukemia (AML) is an aggressive myeloid malignancy with a poor prognosis. Venetoclax (Ven), a BCL2 inhibitor, has shown promising results but often leads to relapse due to mitochondrial dysregulation, particularly due to upregulation of the anti-apoptotic protein MCL1. Overexpression of the transcription factor STAT3 has been linked to poor survival in AML patients. Overexpression of STAT3 in a transgenic murine model induces a myeloid malignancy with a short latency period and inflammatory upregulation. The current study identifies STAT3 upregulation as a key mechanism of Ven resistance. A clinically relevant STAT3 degrader effectively reduces both total and phosphorylated STAT3, corrects mitochondrial structural and functional dysregulation, and induces apoptosis in Ven-resistant AML cell lines. KT-333 significantly decreases STAT3 and MCL1 protein levels and improves survival in Ven-resistant (Ven-Res) AML murine models. In summary, STAT3 hyperactivation is leukemogenic, is further potentiated in Ven-resistance and can be clinically targeted with a novel and specific STAT3 degrader. (Figure presented.)

UR - https://www.scopus.com/pages/publications/105030302621

UR - https://www.scopus.com/pages/publications/105030302621#tab=citedBy

U2 - 10.1038/s41375-026-02883-9

DO - 10.1038/s41375-026-02883-9

M3 - Article

C2 - 41703028

AN - SCOPUS:105030302621

SN - 0887-6924

VL - 40

SP - 717

EP - 729

JO - Leukemia

JF - Leukemia

IS - 4

ER -

A STAT3 degrader demonstrates efficacy in venetoclax resistant acute myeloid leukemia

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this