Frontiers in Anti-Cancer Drug Discovery

Volume: 3

Janus Kinase 2 and Transforming Growth Factor Beta Signal Transduction Targeted Therapies in BCR/ABL-Negative Myeloproliferative Neoplasms

Author(s): Vladan P. Čokić and Juan F. Santibáñez

Pp: 32-108 (77)

DOI: 10.2174/9781608058846114030004

* (Excluding Mailing and Handling)

Abstract

The classic BCR/ABL-negative myeloproliferative neoplasms (MPNs), including polycythaemia vera (PV), essential thrombocythaemia (ЕТ) and primary myelofibrosis (PMF), originate from a stem cell-derived clonal myeloproliferation represented with variable hematopoietic cell lineages and the possibility to convert to PMF and progress into acute myeloid leukemia. Their molecular pathogenesis has been associated with persistent and acquired gain-of-function mutations in the Janus kinase 2 (JAK2) and thrombopoietin receptor (MPL) genes. Furthermore, familial MPNs have an autosomal dominant inheritance with decreased penetrance. Additionally, mutations in TET2, IDH1/2, EZH2, and ASXL1 genes which appear to affect the epigenome of MPN patients have been described. The transforming growth factor-beta (TGF-β) signaling pathway has a defined role in regulating normal hematopoiesis and is frequently dysregulated in hematologic malignancies. During hematopoiesis, the TGF-τ potently inhibits proliferation and stimulates cell differentiation and apoptosis. MPNs are resistant to normal homeostatic regulation by TGF-τ mainly due to mutations or deletion of members of TGF-τ signaling pathways or deregulation by oncoproteins. Despite the heterogeneity and genetic complexity of MPNs, the improvement in understanding of their pathogenetic mechanism of myeloid transformation, coupled with the increasing availability of agents acting as tyrosine kinase inhibitors, facilitated the development of therapeutics capable of suppressing the constitutive activation of the JAK/STAT pathway. In addition, advances in the TGF-τ signaling area enable targeting it for the treatment of hematologic malignancies. In this chapter we will discuss new insights in the molecular pathomechanism of MPN, the new innovative JAK inhibitor drugs and potential therapeutic strategies by targeting TGF-τ signaling as well as the potential combinatory use of JAK inhibitors and TGF-τ signal transduction modulators for the treatment of BCR/ABL-negative MPNs.


Keywords: Angiogenesis, essential thrombocythemia, JAK2, JAK2 inhibitors, JAK-STAT pathway, myeloproliferative neoplasms, polycythemia vera, primary myelofibrosis, therapies, transforming growth factor-beta.

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      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1518
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      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59854122 and j.to_ip >=59854122 )) and ((j.from_date <= 1740496857 and j.to_date >= 1740496857 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 6346) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59854122 and j.to_ip >=59854122 )) and ((j.from_date <= 1740496857 and j.to_date >= 1740496857 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 6346) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59854122 and j.to_ip >=59854122 )) and ((j.from_date <= 1740496857 and j.to_date >= 1740496857 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 6346)
      590μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1549
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` where `b`.`banner_ebook` = 1 and `bd`.`content_type` = 'B' and `bd`.`content_id` = 1495 and `b`.`banner_from_date` <= 1740496857 and `b`.`banner_to_date` >= 1740496857 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.15msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 1495
      • 3: 1740496857
      • 4: 1740496857
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='1efc390979cb40c99300d83af9c018b5'
      270μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\Keywords
    10Keywords.php#?
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        fazBtGH2ZkTcSeD7pirtVBmMeEkQel4JQDbDkjzN
        uc_cart_id
        1efc390979cb40c99300d83af9c018b5
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/6346" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/6346
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:17 [ "x-https" => array:1 [ 0 => "1" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] "priority" => array:1 [ 0 => "u=0, i" ] "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6Im5ScUJjQkZjOFFaRzNkOTN1Yk1kOHc9PSIsInZhbHVlIjoiNURFNzBXTmJVMFRUcWlJdnBIc0hLbndzZTZxS0duZWZqMld4cjB0aFhYVT0iLCJtYWMiOiJlODAwMjQ0ZTU4MzE3MjI2M2ViZDRjOGQ4OTQzMDJiMDNhZmU2OWMxYWQzNGNhYTJjOWYyMjM1MTg1MjFjNTE5IiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6Im5ScUJjQkZjOFFaRzNkOTN1Yk1kOHc9PSIsInZhbHVlIjoiNURFNzBXTmJVMFRUcWlJdnBIc0hLbndzZTZxS0duZWZqMld4cjB0aFhYVT0iLCJtYWMiOiJlODAwMjQ0ZTU4MzE3" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate, br, zstd" ] "sec-fetch-dest" => array:1 [ 0 => "document" ] "sec-fetch-user" => array:1 [ 0 => "?1" ] "sec-fetch-mode" => array:1 [ 0 => "navigate" ] "sec-fetch-site" => array:1 [ 0 => "none" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "sec-ch-ua-platform" => array:1 [ 0 => ""Windows"" ] "sec-ch-ua-mobile" => array:1 [ 0 => "?0" ] "sec-ch-ua" => array:1 [ 0 => ""HeadlessChrome";v="129", "Not=A?Brand";v="8", "Chromium";v="129"" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] ]
        request_cookies
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Tue, 25 Feb 2025 15:20:57 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6ImtLUjZ0cUQzS2pDM09zOWRwLzhDM3c9PSIsInZhbHVlIjoid2dQdHVXSHJlV29zVDZyR0tGak92elpac2Z1RjNZNyttNEUyZU1Pa3RSdnlsb00zUkR5VkZyNUYzczFETi9WSjlnbzRlWFhXOWZLZmxnTnRSOVU4SWF3T0xxR0RHc05ReGQvTVVwS3pYeXpHRkFuTmQxMjVoeVhHclFDZy9SQ2ciLCJtYWMiOiI2MTcxMGNlMzYyMzk5ZTM1ZDZjYTI1MjU3NzVmM2VlMDg2ZDUxMDI0YTk0ODA1Y2FkYjcwZmVmMjllYjZiZTBmIiwidGFnIjoiIn0%3D; expires=Fri, 28 Feb 2025 03:20:57 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6ImtLUjZ0cUQzS2pDM09zOWRwLzhDM3c9PSIsInZhbHVlIjoid2dQdHVXSHJlV29zVDZyR0tGak92elpac2Z1RjNZNyttNEUyZU1Pa3RSdnlsb00zUkR5VkZyNUYzczFETi9WSjlnbzRlW" 1 => "alphaeurekaselectnet_session=eyJpdiI6InllSW9kVTl3aHI0SW8zSVFRNzFWaUE9PSIsInZhbHVlIjoiOFJnUlZaUkltU0MyWnM1dkVlTnZWcTFqeVVXNTJSTFB5VWR0RWlaQlFKdGNoWVhkaUVQNmFBMzNTemU1TzcrWEtTeHBhWGR1Q2pWZlU5SU5xU28vKy9qWUpkekR2MlZGZUxwNXptR0FaRnlTMk00NE9OcDR1TWx4ODUzemduTloiLCJtYWMiOiIyMzY4ZmUyNWEzNThlYTc1ZjgwYWZlMmRkYzExZTNlMDQ3NGJlMDQ4MzY2NTA0NDYyZTkxMTBiMTIzMjIxNGM2IiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6InllSW9kVTl3aHI0SW8zSVFRNzFWaUE9PSIsInZhbHVlIjoiOFJnUlZaUkltU0MyWnM1dkVlTnZWcTFqeVVXNTJSTFB5VWR0RWlaQlFKdGNoWVhkaUVQNmFBMzN" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6ImtLUjZ0cUQzS2pDM09zOWRwLzhDM3c9PSIsInZhbHVlIjoid2dQdHVXSHJlV29zVDZyR0tGak92elpac2Z1RjNZNyttNEUyZU1Pa3RSdnlsb00zUkR5VkZyNUYzczFETi9WSjlnbzRlWFhXOWZLZmxnTnRSOVU4SWF3T0xxR0RHc05ReGQvTVVwS3pYeXpHRkFuTmQxMjVoeVhHclFDZy9SQ2ciLCJtYWMiOiI2MTcxMGNlMzYyMzk5ZTM1ZDZjYTI1MjU3NzVmM2VlMDg2ZDUxMDI0YTk0ODA1Y2FkYjcwZmVmMjllYjZiZTBmIiwidGFnIjoiIn0%3D; expires=Fri, 28-Feb-2025 03:20:57 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6ImtLUjZ0cUQzS2pDM09zOWRwLzhDM3c9PSIsInZhbHVlIjoid2dQdHVXSHJlV29zVDZyR0tGak92elpac2Z1RjNZNyttNEUyZU1Pa3RSdnlsb00zUkR5VkZyNUYzczFETi9WSjlnbzRlW" 1 => "alphaeurekaselectnet_session=eyJpdiI6InllSW9kVTl3aHI0SW8zSVFRNzFWaUE9PSIsInZhbHVlIjoiOFJnUlZaUkltU0MyWnM1dkVlTnZWcTFqeVVXNTJSTFB5VWR0RWlaQlFKdGNoWVhkaUVQNmFBMzNTemU1TzcrWEtTeHBhWGR1Q2pWZlU5SU5xU28vKy9qWUpkekR2MlZGZUxwNXptR0FaRnlTMk00NE9OcDR1TWx4ODUzemduTloiLCJtYWMiOiIyMzY4ZmUyNWEzNThlYTc1ZjgwYWZlMmRkYzExZTNlMDQ3NGJlMDQ4MzY2NTA0NDYyZTkxMTBiMTIzMjIxNGM2IiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6InllSW9kVTl3aHI0SW8zSVFRNzFWaUE9PSIsInZhbHVlIjoiOFJnUlZaUkltU0MyWnM1dkVlTnZWcTFqeVVXNTJSTFB5VWR0RWlaQlFKdGNoWVhkaUVQNmFBMzN" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "fazBtGH2ZkTcSeD7pirtVBmMeEkQel4JQDbDkjzN" "uc_cart_id" => "1efc390979cb40c99300d83af9c018b5" "_previous" => array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/6346" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 15:20:57GET/chapter/63461121912