Interleukin-2 and Tretinoin for Myeloproliferative Neoplasms and to Target Type 1 Calreticulin-Driven Neoplasms: Advancements in Immune Regenerative Medicine

Sep 22, 2026

Stem cells can differentiate into tissue-specific cells, but genetic and epigenetic alterations may transform them into cancer-initiating cells. In myeloproliferative neoplasms (MPN), mutation-bearing cells are suggested to reside as long-term hematopoietic stem cells at the top of the hierarchy. Natural killer cells suppress cancer stem cells via cytotoxicity and cytokines, while interleukin-2 (IL-2) amplifies T-cell activity and NK-cell killing. A case of clinically aggressive Type 1 CALR-mutant MPN showed improved immune function, undetectable CALR mutation levels, reduced symptoms, and lower toxicity using low-dose IL-2 plus oral tretinoin (ATRA).

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

AccessFree to download

Introduction

Stem cells and hematopoietic hierarchy

MPN initiation, progression, and signaling pathways

Driver mutations and CALR Type 1 vs Type 2

Therapy considerations and treatment challenges

Case Report Interleukin-2 and Tretinoin for Myeloproliferative Neoplasms and to Target Type 1 Calreticulin-Driven Neoplasms: Advancements in Immune Regenerative Medicine Dipnarine Maharaj 1, *, Wen Zhang 1, Kawaljit Kaur 2 and Jacqueline Gouvea 1 Academic Editor: Bruno Bonetti Received: 24 December 2025 Revised: 5 March 2026 Accepted: 11 March 2026 Published: 20 March 2026 Copyright: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1 The Maharaj Institute of Immune Regenerative Medicine, Boynton Beach, FL 33437, USA; [zhang.wen81@gmail.com](zhang.wen81@gmail.com) (W.Z.); [jgouvea@bmscti.org](jgouvea@bmscti.org) (J.G.) 2 ImmuneLink, LLC, Riverside, CA 92508, USA; [drkawalmann@g.ucla.edu](drkawalmann@g.ucla.edu) * Correspondence: [dmaharaj@bmscti.org](dmaharaj@bmscti.org); Tel.: +1-(561)752-5522 Abstract Stem cells, also known as progenitor cells, can differentiate into specialized cells for specific tissues. Genetic mutations and epigenetic changes may cause normal stem cells to become cancer-initiating cells. Research indicates that cells acquiring a mutation for myeloproliferative neoplasm (MPN) are likely to be long-term hematopoietic stem cells (LT-HSCs) at the top of the hematopoietic hierarchy. Natural killer (NK) cells play a crucial role in combating cancer by targeting and eliminating cancer stem cells (CSCs) while promoting their maturation. NK cells do this through direct lysis of CSCs or by releasing cytokines like interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), which inhibit tumor growth and metastasis by driving differentiation of CSCs. Interleukin-2 (IL-2) enhances the activity of CD4+ and CD8+ T cells and boosts NK cell cytotoxicity. This study highlights a case of MPN with a more clinically aggressive Type 1 calreticulin (CALR) mutation, where a combination of low-dose IL-2 immunotherapy and targeted therapy with oral tretinoin (all-trans retinoic acid, ATRA, a vitamin A derivative) improved immune cells, particularly NK-cell-mediated destruction of malignant cells, reduced CALR mutation levels to undetectable, and alleviated disease symptoms. The aim is to offer a new, low-toxicity personalized treatment strategy that eradicates cancer-initiating stem cells, reduces side effects, and provides an option for patients with limited conventional therapy alternatives. Keywords: stem cells (SCs); cancer stem cells (CSCs); calreticulin (CALR) mutation; personalized; precision; immunotherapy; targeted therapy; tretinoin; cytokines; interleukin-2 (IL-2); natural killer (NK) cells 1. Introduction Stem cells (SCs) have become a key focus in recent research; they have a remarkable ability to self-renew and differentiate into mature cells specific to various tissue types [1] . Hematopoietic stem cells (HSCs), as multipotent precursors, can self-renew and regenerate the diverse cells of the blood-forming system [2] . The initial cells that acquire a myeloproliferative neoplasm (MPN)-initiating mutation are long-term hematopoietic stem cells (LT-HSCs), located at the top of the hematopoietic hierarchy [3–5] . Unlike acute leukemia, where myeloid progenitor cells gain abnormal self-renewal, MPN initiation and progression depend on cells within the immunophenotypically defined LT-HSC compartment [6–9] . The myeloproliferative leukemia virus oncogene (MPL), also known as the thrombopoietin receptor gene, plays a crucial role as a growth factor receptor in MPN development [10] . When activated, MPL signaling triggers molecular events that give MPN stem cells a clonal advantage in the bone marrow [11] . MPNs share clinical and biological traits, including activation of the Janus Kinase–Signal Transducer and Activator of Transcription (JAK-STAT) pathway, which regulates vital cellular functions like growth, survival, and differentiation, p

FAQs

What roles do natural killer (NK) cells play in targeting cancer stem cells in this study?

NK cells target and eliminate cancer stem cells either by direct lysis or by releasing cytokines such as interferon-gamma and TNF-alpha, which suppress tumor growth and support differentiation of cancer stem cells.

How does IL-2 contribute to immune activity against myeloproliferative neoplasms in the case?

IL-2 enhances CD4+ and CD8+ T-cell activity and increases NK-cell cytotoxicity, strengthening immune-mediated destruction of malignant cells.

What treatment combination is highlighted for a Type 1 CALR-driven MPN case?

The case emphasizes low-dose IL-2 immunotherapy combined with targeted oral tretinoin (all-trans retinoic acid, ATRA), aiming to eradicate cancer-initiating stem cells while reducing toxicity and symptoms.

Sep 22, 2026

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