JAKs in Leukemias and Lymphomas

The first suggestion for a role of constitutively active JAK in human cancer came from a study of patients with B-precursor lymphoblastic acute leukemia (pre-B ALL) in relapse (74). Tumor-derived cell lines harbored constitutively activated JAK2, and AG490, a PTK inhibitor shown to be effective against JAKs, prevented the tumor cells to engraft in SCID mice (see Section 5) (75). Similar results were obtained with pre-B ALL cell lines harboring an 11q23 translocation

Table 2

JAK Associated Hematological Malignancies

Type of altered

Disease

Kinase

activity

implicated

References

Leukemias

JAK2

Persistent activation

Precursor-B ALL

(74,76)

(autocrine cytokine

production, Btk,

Bcr-Abl)

JAK2

TEL-JAK fusion

T-ALL, Precursor-B

(77,78)

protein (chromosomal

ALL, CML

translocation)

JAK2

Bcr/JAK2 fusion

CML

(82)

protein (chromosomal

translocation)

JAK1

Constitutive activation

JAK2

(cytokine production,

Myeloid leukemia

(19,93)

Bcr-Abl)

(cell lines)

JAK1

Constitutive activation

Adult T-cell

(34,91,92)

JAK3

(cytokine production,

leukemia/

defect in negative

lymphoma

regulation)

(HTLV-1

transformed)

Lymphomas

JAK1

Constitutive activation

B-lymphoblastoid

(94)

(autocrine IL-10)

cell lines

(EBV-positive)

JAK2

Increased expression

Hodgkin's lymphoma

(83,84)

(gene amplification)

JAK2

Increased expression

Diffuse large B-cell

(85)

(gene amplification)

lymphoma

JAK2

Increased expression

Mediastinal large

(86,87,88)

(gene amplification,

B-cell lymphoma

IL-4?)

JAK3

Constitutive activation

Cutaneous T-cell

(89,90)

lymphoma

JAK1

Constitutive activation

LSTRA T-cell

(53)

JAK2

(Lck overexpression)

lymphoma

(mouse cell line)

JAK2

Constitutive activation

NPM/ALK positive

(21,95,96)

JAK3

(activated ALK)

anaplastic large

cell lymphoma

(Continued)

Table 2 (Continued)

Kinase

Type of altered activity

Disease implicated

Multiple myeloma

Defect in negative regulation

Hemophagocytic/ lymphohistiocytosis

(32)

JAK1 JAK2 TYK2

Persistent activation (cytokine/IL-6-mediated, defect in negative regulation)

Multiple myeloma cell lines and primary tumor cells

(98,110,111, 112,118)

JAK, janus kinase; ALL, acute lymphoblastic leukemia; CML, chronic myeloid leukemia; HTLV-1, human T-cell lymphotropic virus type-1; EBV, Epstein-Barr virus; ALK, anaplastic lymphoma kinase; NPM, nucleophosmin.

JAK, janus kinase; ALL, acute lymphoblastic leukemia; CML, chronic myeloid leukemia; HTLV-1, human T-cell lymphotropic virus type-1; EBV, Epstein-Barr virus; ALK, anaplastic lymphoma kinase; NPM, nucleophosmin.

or the Philadelphia chromosome. In these cases, the Btk tyrosine kinase and Bcr-Abl were found to associate with JAK2 and suggested to be involved in JAK2 activation. AG490 inhibited JAK2 phosphorylation and cell growth (76).

Direct evidence of the concept that dysregulation of JAKs can cause cellular transformation comes from the identification of TEL/JAK fusion proteins in lymphoid leukemias and a case of atypical CML (77,78). In these cases, chromosomal translocations were involved that led to the production of a chimeric protein containing the oligomerization domain of the translocated ets leukemia (TEL) protein, a member of the ETS transcription factor family, fused to the catalytic JH1 domain of JAK2 (Fig. 3). As a result of this fusion, the kinase becomes constitutively activated (79). Moreover, it has been demonstrated that the TEL/JAK chimera was able to transform Ba/F3 cells and render them factor-independent (77,79,80). Mice transplanted with the retrovirus expressing the fusion protein develop a fatal mixed myeloproliferative and lymphoprolifera-tive disorder (80). Importantly, TEL/JAK transgenic mice develop T-cell leukemia with constitutive activation of STAT1 and STAT5 in leukemic tissues (81). A similar chromosomal translocation, t(9;22)(p24;q11), involves JAK2 fused to the BCR region, and was found in cases of Bcr-Abl negative CML (82).

Another genetic defect that leads to deregulated JAK expression involves gene amplification. In primary Hodgkin's lymphoma cells and cell lines, an increased copy number of chromosomal sequences spanning the JAK2 gene were identified (83,84). Genomic amplification of the JAK2 gene was also evident in a case of diffuse large B-cell lymphoma, which resulted in a high expression of the respective JAK2 mRNA transcript (85). In another aggressive non-Hodgin's lymphoma (NHL), mediastinal large B-cell lymphoma, gains in chromosome arm 9p that include JAK2 gene amplification and high expression levels of JAK2 were found (86-88).

Fig. 3. Translocated ETS leukemia/Janus kinase-2 (TEL/JAK) fusion proteins in acute lymphoid leukemia (ALL) and chronic myeloid leukemia (CML). Expression of the TEL/JAK fusion protein is the result of a t(9;12)(p24;p13) chromosomal translocation. The amino acid positions of the fusions are indicated by numbers. HLH, Helix-Loop-Helix oligomerization domain. Adapted from ref. 62.

Fig. 3. Translocated ETS leukemia/Janus kinase-2 (TEL/JAK) fusion proteins in acute lymphoid leukemia (ALL) and chronic myeloid leukemia (CML). Expression of the TEL/JAK fusion protein is the result of a t(9;12)(p24;p13) chromosomal translocation. The amino acid positions of the fusions are indicated by numbers. HLH, Helix-Loop-Helix oligomerization domain. Adapted from ref. 62.

In many cases, however, the precise mechanisms underlying constitutive JAK activation have not been identified. In a study of cutaneous T-cell lymphomas, the data suggest that the progression from indolent to aggressive T-cell lymphomas may involve a switch from factor-dependent to constitutive JAK3 activation (89). In tumor cell lines from a patient with mycosis fungoides, a slowly migrating isoform of STAT3 was found to be constitutively activated and associated with JAK3 (90). Similarly, the progression of adult T-cell leukemia/lymphoma (ATLL) seems to be correlated with a gradual onset of constitutive JAK1 and JAK3 activation combined with loss of IL-2 dependence (91,92). Constitutive JAK phosphorylation was also observed in myeloid and B-lymphoblastoid cell lines (19,93,94). For some of these cases, autocrine cytokine production has been suggested as the cause of JAK activation. Very recent studies suggest a role for JAK kinases in the pathophysiology of NPM/ALK positive ALCL. Constitutive JAK2 and JAK3 phosphorylation and physical association with NPM-ALK was observed in ALCL cells, suggesting a role for the ALK tyrosine kinase in JAK activation (21,95,96). However, the role of JAKs for STAT activation and NPM/ALK-mediated transformation is unclear and further studies are needed.

Defects in the negative regulation of JAKs may also contribute to malignant proliferation. Expression of the phosphatase SHP-1 is decreased in more than 90% of hematopoietic-related and some nonhematopoietic tumor cell lines and tissues including B- and T-cell lymphomas. The diminished or abolished SHP-1 expression could be because of a mutation of the SHP-1 gene, methylation of the promoter region of the SHP-1 gene or posttranscriptional regulation of SHP-1 protein synthesis (reviewed in ref. 97). For example, expression of SHP-1 is downregulated in a number of IL-2-independent human T-cell lymphotrophic virus type-1 (HTLV-1) transformed T-cell lines that exhibit constitutive JAK/STAT, thereby contributing to HTLV-1-mediated T-cell transformation (34). Another mechanism is the lack of interaction between the phosphatase and JAK, shown for SHP-1 and TYK2 in familial hemophagocytic lymphohistiocytosis (32). Nonfunctional SOCS proteins owing to methylation were observed in multiple myeloma (MM) and acute myeloid leukemia (98,99). Very recently, somatic SHP-2 mutations have been found in approx 30% of sporadic juvenile myelomonocytic leukemia (100).

In many primary lymphoid and myeloid leukemia cells, constitutively activated STAT proteins have been found; however, the underlying mechanisms or the JAKs involved have not been identified (101-104). It cannot be excluded that, at least in some cases, other PTKs than JAKs, i.e., kinases of the Src family, might be responsible for STAT phosphorylation (12,105). Other studies, however, do suggest the involvement of JAKs by using the JAK inhibitor AG490. In large granular lymphocyte (LGL) leukemia and primary effusion lymphoma (PEL), AG490 induced apoptosis that was accompanied by a decrease or abrogation of STAT activation (106,107).

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