But how do normal immune cells become leukemic? Understanding the pathways:

Cancer development is an extremely complex process in that it normally required a large accumulation of mutations within multiple cells to induce pathology. But when these mutations occur in vital regulalrtoy pathways within a cell, things may rapidly get out of hand. In cancer research, understanding the molecular pathways in which genes are dysregulated is a vital part of developing cures for patients. Here we will look into six pathways - RAS-MAPK, PI3-AKT, JAK-STAT, HIF-1α, Gsk-3β-, NF-κB - which are commonly dysregulated in ALL, as well as discuss their importance for normal cell survival and how their dysregulation leads to the symptoms seen in patients with ALL.

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          Illustration of signaling diagram by Pedro Ramírez adapted from 6, 7, 8, and 9.

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• RAS-MAPK:

The Ras mitogen-activated kinase pathway is a key regulator of normal cell survival, proliferation, and general homeostasis. Mitogens are those molecule which promote cells to divide, continuing to go through the cell cycle.  When a mitogen binds to an extracellular receptor, the Ras GTPase molecule is a activated which in turn actives RAF, a protein kinase, proteins which add a phosphate group to another protein, usually leading to activation. This activation by Ras is known as the kinase cascade as RAF activates MEK, MEK activates Erk, and Erk travels to the nucleus to activate transcription factors to induce DNA replication (A). Induction of these transcription factors promote increased DNA replication, signaling the cell to continue diving [1]. 

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• PI3K-AKT/JAK-STAT: 

Phosphatidylinositol 3-kinase (PI3K) pathway is another key regulatory pathway in maintaining proper cell homeostasis. In normal cells which need to divide, the intracellular PI3K-AKT pathway is activated by ligand binding, causing a activation of JAK1 (Janus Kinase). PI3K is activated by JAK1, and PI3K, a kinase, activates AKT by phosphorylation, another well-known protein kinase. AKT kinase leads to activation of mTOR which diverges in two ways- one to increase transcription or two, to activate the HIF-1α pathway (B). JAK1 activation in the PI3K often leads to activation of the JAK-STAT pathway as well, another important pro-survival pathway. Upon activation, two JAK1 kinases active each other via cross phosphorylation, allowing each active JAK to phosphorylate a STAT or Signal Transducer and Activator of Transcription protein (C). STAT will enter the nucleus and promote DNA transcription [1].  

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• HIF-1α: 

The hypoxia-inducible factor 1 alpha is a master transcription factor regulator, very important in singing in the event of hypoxia, or oxygen deprived states, within a cell, functioning as a cell survival regulator when active. One way HIF-1α may be activated is through mTOR activity as depicted above (D). Upon activation of HIF-1α, transcription factors localize to the nucleus where HIF-1α and HIF-1β bind with another protein p300 and induce transcription, signaling the cell to divide. However, the HIF-1α protein also signals for Mdm2 expression, a ubiquitin ligase which regulates the amount of p53 by degradation. P53 is a negative regulator of transcription, thus in this way HIF-1α may also induce transcription. VHL is another ubiquitin ligase which binds HIF-1α under non-hypoxic conditions and targets it for degradation, keeping the homeostatic balance within a cell [1]. 

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• Gsk-3β/NF-κB: 

Glycogen synthase kinase-3β (Gsk-3β) activation is a key regulator in the NF-κB pathway, leading to anti-apoptotic effects, cell survival, and other homeostatic processes within the cell (E). The Gsk-3β pathway activation and role in NF-κB signaling is not extremely well understood. The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex which regulates DNA replication and cell survival (like angiogenesis, the creation of new blood vessels). A three protein complex association upon action of NF-κB and signal another protein complex known as CBM (F). The CBM complex diverges to activate other kinase proteins which both activate IκBα/NF-κB complexes which localize to the nucleus and induce transcription [1].

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