Mathematical Modeling of MPNs Offers Understanding and Decision Support for Personalized Treatment

(1) Background: myeloproliferative neoplasms (MPNs) are slowly developing hematological cancers characterized by few driver mutations, with JAK2V617F being the most prevalent. (2) Methods: using mechanism-based mathematical modeling (MM) of hematopoietic stem cells, mutated hematopoietic stem cells, differentiated blood cells, and immune response along with longitudinal data from the randomized Danish DALIAH trial, we investigate the effect of the treatment of MPNs with interferon-α2 on disease progression. (3) Results: At the population level, the JAK2V617F allele burden is halved every 25 months. At the individual level, MM describes and predicts the JAK2V617F kinetics and leukocyte- and thrombocyte counts over time. The model estimates the patient-specific treatment duration, relapse time, and threshold dose for achieving a good response to treatment. (4) Conclusions: MM in concert with clinical data is an important supplement to understand and predict the disease progression and impact of interventions at the individual level.

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Distinct effects of concomitant Jak2V617F expression and Tet2 loss in mice promote disease progression in myeloproliferative neoplasms

Blood ◽

10.1182/blood-2014-04-567024 ◽

2015 ◽

Vol 125 (2) ◽

pp. 327-335 ◽

Cited By ~ 49

Author(s):

Edwin Chen ◽

Rebekka K. Schneider ◽

Lawrence J. Breyfogle ◽

Emily A. Rosen ◽

Luke Poveromo ◽

...

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Competitive Advantage ◽

Disease Progression ◽

Myeloproliferative Neoplasms ◽

Loss Of Function ◽

Hematopoietic Stem ◽

Key Points ◽

Promote Disease Progression

Key Points Tet2 loss of function confers a strong functional competitive advantage to Jak2V617F-mutant hematopoietic stem cells. Jak2V617F expression and Tet2 loss generate distinct and nonoverlapping transcriptional programs in hematopoietic stem cells.

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Hematopoietic stem cells, progenitor cells and leukemic stem cells in adult myeloproliferative neoplasms

Leukemia & Lymphoma ◽

10.3109/10428194.2012.734615 ◽

2012 ◽

Vol 54 (5) ◽

pp. 922-933 ◽

Cited By ~ 5

Author(s):

Ashley P. Ng

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Progenitor Cells ◽

Myeloproliferative Neoplasms ◽

Leukemic Stem Cells ◽

Hematopoietic Stem

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The Tao of Hematopoietic Stem Cells: Toward a Unified Theory of Tissue Regeneration

The Scientific World JOURNAL ◽

10.1100/tsw.2002.162 ◽

2002 ◽

Vol 2 ◽

pp. 983-995 ◽

Cited By ~ 4

Author(s):

Kevin D. Bunting ◽

Robert G. Hawley

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Hematopoietic Stem Cells ◽

Adult Stem Cells ◽

Developmental Plasticity ◽

Marrow Cell ◽

Cell Types ◽

Therapeutic Benefit ◽

Hematopoietic Stem ◽

The Individual

Hematopoietic stem cells (HSCs) are the best studied of the tissue-specific stem cells. By definition, HSCs have long been regarded as restricted to formation of blood cells of both the lymphoid and myeloid lineages. HSCs residing in the bone marrow microenvironment have self-renewal capacity and can repopulate the hematopoietic system of irradiated transplant recipients for the lifetime of the individual. Therefore, HSCs are extremely important targets for gene therapy applications aimed toward the treatment of inherited and acquired blood disorders. However, recent studies have suggested that a subpopulation of HSCs may have the ability to contribute to diverse cell types such as hepatocytes, myocytes, and neuronal cells, especially following induced tissue damage. Preclinical amelioration of liver disease and myocardial infarcts by HSC-enriched bone marrow cell populations raises the possibility that HSC transplants have the potential to provide therapeutic benefit for a wide variety of diseases. These surprising findings contradict the dogma that adult stem cells are developmentally restricted. Extrapolation of these findings to the clinic will be facilitated by prospective identification of the stem cells that possess this developmental plasticity. Furthermore, characterization of the signaling pathways and molecular determinants regulating the remarkable transdifferentiation capacity of these stem cells may provide insight into novel approaches for modulating frequency of differentiative potential.

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The thrombopoietin receptor, MPL, is critical for development of a JAK2V617F-induced myeloproliferative neoplasm

Blood ◽

10.1182/blood-2014-07-587238 ◽

2014 ◽

Vol 124 (26) ◽

pp. 3956-3963 ◽

Cited By ~ 40

Author(s):

Veena Sangkhae ◽

S. Leah Etheridge ◽

Kenneth Kaushansky ◽

Ian S. Hitchcock

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Myeloproliferative Neoplasms ◽

Myeloproliferative Neoplasm ◽

Hematopoietic Stem ◽

Thrombopoietin Receptor ◽

Key Points

Key Points MPL is essential for the development of JAK2V617F-positive myeloproliferative neoplasms in vivo. Ablation or reduction of Mpl significantly reduces the pool of neoplastic hematopoietic stem cells.

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Deletion of PTPN1 Promotes the Development of Myelofibrosis

Blood ◽

10.1182/blood.v128.22.795.795 ◽

2016 ◽

Vol 128 (22) ◽

pp. 795-795

Author(s):

Fatoumata Jobe ◽

Bhumika Patel ◽

Hideki Makishima ◽

Bartlomiej P Przychodzen ◽

Robert E Hutchison ◽

...

Keyword(s):

Stem Cells ◽

Tumor Suppressor ◽

Hematopoietic Stem Cells ◽

Conflicts Of Interest ◽

Myeloproliferative Neoplasms ◽

Tyrosine Phosphatase ◽

Wild Type ◽

Hematopoietic Stem ◽

Flow Cytometric ◽

Obesity And Diabetes

Abstract Deletion of chromosome 20q [del(20q)] is a common chromosomal abnormality associated with myeloid neoplasms including myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS), MDS/MPN overlap disorders and acute myeloid leukemia (AML). The del(20q) lesion is often associated with myeloproliferative features; it is present in patients with myelofibrosis (MF) at a high frequency (24%) and thus considered to be one of the most frequent cytogenetic abnormalities in MF (Wassie et al., Br J Haematol. 2015). The del(20q) lesion can also coexist with JAK2V617F mutation in MPN/MF. However, the target tumor-suppressor gene(s) within chromosome 20q involved in the pathogenesis of MF remains unknown. The PTPN1 locus maps to human chromosome 20q13.1-q13.2. PTPN1 (also known as PTP1B) is a ubiquitously expressed non-receptor tyrosine phosphatase that has been linked to metabolism and cancer. Mice deficient in Ptpn1 exhibit resistance to diet-induced obesity and diabetes. Both oncogenic and tumor suppressor functions for PTPN1 have been suggested. PTPN1 can negatively regulate the JAK/STAT signaling, which is frequently found activated in MPN. Here, we report the identification and functional consequences of PTPN1 deletion in the pathogenesis of MF. Deletion of PTPN1 was identified in 14% cases of MF. Conditional deletion of Ptpn1 in the mouse hematopoietic compartment resulted in significant increases in white blood cell and neutrophil counts in the peripheral blood and enlargement of spleen size. Flow cytometric analyses showed significant expansion of myeloid (Gr-1+/Mac-1+) precursors in the bone marrow (BM) and spleens of Ptpn1-deleted mice compared with control animals. Megakaryocytic (CD41+/CD61+) precursors were also significantly increased in the spleens of Ptpn1-deleted mice. Flow cytometric analyses also revealed significant increases in absolute numbers of LSK cells (Lin-Sca1+c-kit+) and its subsets including long-term hematopoietic stem cells (LT-HSC), short-term HSC (ST-HSC) and multi-potent progenitors (MPP) in the spleens of Ptpn1-deleted mice. Hematopoietic progenitor colony assays showed significant increases in myeloid (CFU-GM) and megakaryocytic (CFU-Mk) colonies in the BM of Ptpn1-deleted mice compared with control mice BM. Histopathologic analysis demonstrated fibrosis (grade 2) in the BM and spleens of Ptpn1-deleted mice at 52 weeks after induction, whereas control animals did not exhibit fibrosis at that age. Together, these results suggest that deletion of Ptpn1 induces an MPN-like phenotype, which progresses to MF over time. Moreover, transplantation of Ptpn1-deficient BM into lethally irradiated wild-type animals resulted in fibrosis at 18 weeks after transplantation, demonstrating that the effect of Ptpn1 loss in the development of myelofibrosis is cell-intrinsic. Competitive repopulation assays using BM from control or Ptpn1-deficient (CD45.2+) mice with wild type congenic (CD45.1+) mice showed that deletion of Ptpn1 enhances the repopulation capacity of hematopoietic stem cells. Biochemical analyses revealed that depletion of Ptpn1 enhanced JAK2/STAT5, AKT and ERK signaling in the BM of Ptpn1-deleted mice. Furthermore, we observed that deletion of Ptpn1 in Jak2V617F knock-in mice accelerates the development of myelofibrosis. In conclusion, our results establish a tumor-suppressor function for PTPN1 in MF. Disclosures No relevant conflicts of interest to declare.

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Synergism between interleukin-6 and interleukin-3 in supporting proliferation of human hematopoietic stem cells: comparison with interleukin-1 alpha

Blood ◽

10.1182/blood.v71.6.1759.bloodjournal7161759 ◽

1988 ◽

Vol 71 (6) ◽

pp. 1759-1763 ◽

Cited By ~ 1

Author(s):

AG Leary ◽

K Ikebuchi ◽

Y Hirai ◽

GG Wong ◽

YC Yang ◽

...

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Interleukin 6 ◽

Colony Formation ◽

Interleukin 1 ◽

Blast Cell ◽

Hematopoietic Stem ◽

Interleukin 3 ◽

The Individual ◽

Cell Colony

Currently available evidence suggests that in the steady state, the majority of hematopoietic stem cells are dormant in cell cycle and reside in the so-called G0 period. Studies in our laboratory indicated that once a stem cell leaves G0, its subsequent proliferation requires the presence of interleukin-3 (IL-3). Recently it was reported that interleukin-1 (IL-1) may stimulate stem cells to become sensitive to IL- 3. In a separate study, we observed that interleukin-6 (IL-6, also known as B cell stimulatory factor-2/interferon beta 2) possesses synergism with IL-3, shortening the G0 period of murine hematopoietic stem cells. We report here that human IL-6 and IL-3 act synergistically in support of the proliferation of progenitors for human blast cell colonies and that IL-1 alpha reveals no synergism with IL-3 when tested against purified human marrow progenitors. Panned My-10+ human marrow cells were plated in culture and on day 14 of incubation, either IL-3, IL-6, IL-1 alpha or a combination of these factors was added to the cultures. Blast cell colony formation was analyzed daily between days 18 and 32 of culture. IL-6 or IL-1 alpha alone failed to support blast cell colony formation. In the presence of IL-3 alone, blast cell colonies continued to emerge between days 21 and 27. When a combination of IL-3 and IL-6 was added, blast cell colonies developed earlier than in cultures with IL-3 alone and twice as many blast cell colonies were identified. IL-1 alpha failed to augment IL-3-dependent blast cell colony formation. Replating studies of the individual blast cell colonies revealed various types of single as well as multilineage colonies. These observations suggest that IL-6 shortens the G0 period of human hematopoietic stem cells and that the reported synergistic activities of IL-1 on primitive hematopoietic cells may be indirect.

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Synergism between interleukin-6 and interleukin-3 in supporting proliferation of human hematopoietic stem cells: comparison with interleukin-1 alpha

Blood ◽

10.1182/blood.v71.6.1759.1759 ◽

1988 ◽

Vol 71 (6) ◽

pp. 1759-1763 ◽

Cited By ~ 182

Author(s):

AG Leary ◽

K Ikebuchi ◽

Y Hirai ◽

GG Wong ◽

YC Yang ◽

...

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Interleukin 6 ◽

Colony Formation ◽

Interleukin 1 ◽

Blast Cell ◽

Hematopoietic Stem ◽

Interleukin 3 ◽

The Individual ◽

Cell Colony

Abstract Currently available evidence suggests that in the steady state, the majority of hematopoietic stem cells are dormant in cell cycle and reside in the so-called G0 period. Studies in our laboratory indicated that once a stem cell leaves G0, its subsequent proliferation requires the presence of interleukin-3 (IL-3). Recently it was reported that interleukin-1 (IL-1) may stimulate stem cells to become sensitive to IL- 3. In a separate study, we observed that interleukin-6 (IL-6, also known as B cell stimulatory factor-2/interferon beta 2) possesses synergism with IL-3, shortening the G0 period of murine hematopoietic stem cells. We report here that human IL-6 and IL-3 act synergistically in support of the proliferation of progenitors for human blast cell colonies and that IL-1 alpha reveals no synergism with IL-3 when tested against purified human marrow progenitors. Panned My-10+ human marrow cells were plated in culture and on day 14 of incubation, either IL-3, IL-6, IL-1 alpha or a combination of these factors was added to the cultures. Blast cell colony formation was analyzed daily between days 18 and 32 of culture. IL-6 or IL-1 alpha alone failed to support blast cell colony formation. In the presence of IL-3 alone, blast cell colonies continued to emerge between days 21 and 27. When a combination of IL-3 and IL-6 was added, blast cell colonies developed earlier than in cultures with IL-3 alone and twice as many blast cell colonies were identified. IL-1 alpha failed to augment IL-3-dependent blast cell colony formation. Replating studies of the individual blast cell colonies revealed various types of single as well as multilineage colonies. These observations suggest that IL-6 shortens the G0 period of human hematopoietic stem cells and that the reported synergistic activities of IL-1 on primitive hematopoietic cells may be indirect.

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Functional interdependence of hematopoietic stem cells and their niche in oncogene promotion of myeloproliferative neoplasms: the 159th biomedical version of “it takes two to tango”

Experimental Hematology ◽

10.1016/j.exphem.2018.12.004 ◽

2019 ◽

Vol 70 ◽

pp. 24-30 ◽

Cited By ~ 3

Author(s):

Huichun Zhan ◽

Kenneth Kaushansky

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Myeloproliferative Neoplasms ◽

Hematopoietic Stem

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The microenvironment in human myeloid malignancies: emerging concepts and therapeutic implications

Blood ◽

10.1182/blood-2016-11-696070 ◽

2017 ◽

Vol 129 (12) ◽

pp. 1617-1626 ◽

Cited By ~ 58

Author(s):

Hind Medyouf

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Hematopoietic Stem Cells ◽

Myeloproliferative Neoplasms ◽

Bone Marrow Niche ◽

Hematopoietic Stem ◽

Myeloid Malignancies ◽

Communication Modalities ◽

Hematopoietic Niche ◽

Acute Myeloid

Abstract Similar to their healthy counterpart, malignant hematopoietic stem cells in myeloid malignancies, such as myeloproliferative neoplasms, myelodysplastic syndromes, and acute myeloid leukemia, reside in a highly complex and dynamic cellular microenvironment in the bone marrow. This environment provides key regulatory signals for and tightly controls cardinal features of hematopoietic stem cells (HSCs), including self-renewal, quiescence, differentiation, and migration. These features are essential to maintaining cellular homeostasis and blood regeneration throughout life. A large number of studies have extensively addressed the composition of the bone marrow niche in mouse models, as well as the cellular and molecular communication modalities at play under both normal and pathogenic situations. Although instrumental to interrogating the complex composition of the HSC niche and dissecting the niche remodeling processes that appear to actively contribute to leukemogenesis, these models may not fully recapitulate the human system due to immunophenotypic, architectural, and functional inter-species variability. This review summarizes several aspects related to the human hematopoietic niche: (1) its anatomical structure, composition, and function in normal hematopoiesis; (2) its alteration and functional relevance in the context of chronic and acute myeloid malignancies; (3) age-related niche changes and their suspected impact on hematopoiesis; (4) ongoing efforts to develop new models to study niche-leukemic cell interaction in human myeloid malignancies; and finally, (5) how the knowledge gained into leukemic stem cell (LSC) niche dependencies might be exploited to devise novel therapeutic strategies that aim at disrupting essential niche-LSC interactions or improve the regenerative ability of the disease-associated hematopoietic niche.

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